Pathophysiologic and therapeutic implications of adrenomedullin in cardiovascular disorders

Pharmacology & Therapeutics 111 (2006) 909 – 927 www.elsevier.com/locate/pharmthera

Associate editor: F. Brunner

Pathophysiologic and therapeutic implications of adrenomedullin in cardiovascular disorders Toshihiko Ishimitsu ⁎, Hidehiko Ono, Junichi Minami, Hiroaki Matsuoka Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan

Abstract Adrenomedullin (AM) is a vasodilator peptide that originally isolated from pheochromocytoma tissue. However, the mRNA is expressed in the normal adrenal gland, heart, kidney and blood vessels. The human AM gene is located in the short arm of chromosome 11 and is composed of 4 exons. There are 2 single nucleotide polymorphisms in introns 1 and 3, and the 3′-end of the AM gene is flanked by a microsatellite marker of cytosine-adenine repeats that is associated with an increased risk of developing hypertension and diabetic nephropathy. AM gene expression is promoted by various stimuli, including inflammation, hypoxia, oxidative stress, mechanical stress and activation of the renin-angiotensin and sympathetic nervous systems. The AM gene promoter region possessed binding site for several transcription factors, including nuclear factor for interleukin-6 expression (NF-IL6) and activator protein 2 (AP-2). Further, plasma AM levels are increased in patients with various cardiovascular diseases, including hypertension, heart failure and renal failure. These findings suggest that AM plays a role in the development of or response to cardiovascular disease. Indeed, experimental and clinical studies have demonstrated that systemic infusion of AM may have a therapeutic effect on myocardial infarction, heart failure and renal failure. Further, vasopeptidase inhibitors which augment the bioactivity of endogenous AM may benefit patients with hypertension and arteriosclerosis. Finally, the angiogenic and cytoprotective properties of AM may have utility in revascularization and infarcted myocardium and ischemic limbs. Because of the potential clinical benefits of AM, indications for use and optimal dosing strategies should be established. © 2006 Elsevier Inc. All rights reserved. Keywords: Adrenomedullin; Gene polymorphism; Cardiovascular disease; Gene therapy; Cell transplantation Abbreviations: AM, adrenomedullin; AP-1, activator protein-1; AP-2, activator protein-2; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; CGRP, calcitonin gene related peptide; CL, calcitonin receptor-like receptor; CRE, cyclic adenosine monophosphate responsive element; HIF-1, hypoxia-inducible factor-1; MAPK, mitogen-activated protein kinases; NF-IL6, nuclear factor for interleukin-6 expression; NO, nitric oxide; PAMP, proadrenomedullin N-terminal 20 peptide; RAMP, receptor-activity modifying proteins; SSRE, shear stress responsive element.

Contents 1. 2. 3.

4. 5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . Chemical structure of adrenomedullin and related peptides Structure and variation of the human adrenomedullin gene 3.1. Gene structure . . . . . . . . . . . . . . . . . . . 3.2. Variation of the human adrenomedullin gene . . . . 3.2.1. Microsatellite DNA polymorphisms . . . . 3.2.2. Single nucleotide polymorphisms . . . . . Receptor and signal transduction. . . . . . . . . . . . . . Biological actions . . . . . . . . . . . . . . . . . . . . . 5.1. Vascular action . . . . . . . . . . . . . . . . . . .

⁎ Corresponding author. Tel.: +81 282 87 2149; fax: +81 282 86 1596. E-mail address: [email protected] (T. Ishimitsu). 0163-7258/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.pharmthera.2006.02.004

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5.2. Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Kidney . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Lung . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5. Central nervous system . . . . . . . . . . . . . . . . . . . . . . . . . . 5.6. Endocrine system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7. Mitogenesis and apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . 5.8. Anti-oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Regulation of production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Analysis of promoter activity . . . . . . . . . . . . . . . . . . . . . . . 6.2. Factors regulating AM production . . . . . . . . . . . . . . . . . . . . . 6.2.1. Inflammatory cytokines and nitric oxide . . . . . . . . . . . . . 6.2.2. Hypoxia, ischemia and oxidative stress. . . . . . . . . . . . . . 6.2.3. Mechanical stimuli . . . . . . . . . . . . . . . . . . . . . . . . 6.2.4. Renin-angiotensin system and the sympathetic nervous systems . 6.2.5. Other endocrine factors . . . . . . . . . . . . . . . . . . . . . . 6.2.6. Oncogenes and carcinogens . . . . . . . . . . . . . . . . . . . 7. Pathophysiologic implications and therapeutic possibilities . . . . . . . . . . . . 7.1. Hypertension. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2. Heart failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3. Myocardial infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4. Renal failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.5. Pulmonary hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . 7.6. Gene therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.7. Cell transplantation therapy . . . . . . . . . . . . . . . . . . . . . . . . 8. Conclusions and future perspectives . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Adrenomedullin (AM) is a potent vasodilator peptide that was originally isolated from pheochromocytoma tissue (Kitamura et al., 1993a). However, subsequent studies detected endogenous expression of AM in several normal tissues, including the adrenal gland, heart, kidney and blood vessels (Kitamura et al., 1993b), as well as relatively high plasma levels of circulating AM (Kitamura et al., 1994a). In fact, we and other investigators have reported that plasma AM levels are increased in the context of hypertension, heart failure, renal failure and sepsis (Ishimitsu et al., 1994a; Nishikimi et al., 1995; Hirata et al., 1996; Nishio et al., 1997; Ishimitsu et al., 1999). This led some investigators to speculate that AM could play a pathophysiologic role in the development of or response to cardiovascular disease. In addition to its vasodilatory properties, AM produces disparate biological effects in the cardiovascular, respiratory, renal, immune and neuroendocrine systems. Hinson et al. observed that the actions of AM are generally protective and beneficial to the organs and tissues, (e.g., vasodilation, natriuresis and anti-inflammation) (Hinson & Smith, 2000) and suggested that increased AM expression or activity could act as a compensatory response to end-organ injury or dysfunction and may represent a target molecule for therapeutic strategies. AM has been the subject of increasing investigation. Fig. 1 shows the progression in the number of AM-related scientific papers published annually since its discovery in 1993; more than 100 original English-language articles have been published

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914 914 914 914 914 914 915 915 915 916 916 916 916 917 917 917 918 918 919 919 919 920 920 921 921 921

every year since 1997. The present material will review the biochemical characteristics and pathophysiologic implications of AM as well as the pharmacologic properties and therapeutic potential of AM. 2. Chemical structure of adrenomedullin and related peptides Human AM consists of 52 amino acid residues. Cysteine residues, located at positions 16 and 21 from the N-terminus, are bound by disulfide linkage, forming a ring structure composed of 6 amino acids (Kitamura et al., 1993a). AM is thought to 200

Number of Articles

1. Introduction

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150

100

50

0

93

94

95

96

97

98

99

00

01

02

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Year Fig. 1. Annual changes in the number of original English language articles regarding adrenomedullin published in scientific journals.

T. Ishimitsu et al. / Pharmacology & Therapeutics 111 (2006) 909–927

belong to a peptide superfamily that includes the potent vasodilator, calcitonin gene related peptide (CGRP) and amylin, a protein product of the β cells of the pancreas Langerhans islands that is co-released with insulin. Two groups have recently identified a new peptide, adrenomedullin-2 (AM-2) or intermedin, that also belongs to this superfamily (Roh et al., 2004; Takei et al., 2004). The amino acid sequences of these peptides are illustrated in Fig. 2. The AM protein sequences show various degrees of homology with those of CGRP (24%), amylin (22%), AM-2 (34%). Further, all of these proteins possess the 6 amino acid ring structure near the N-terminus as well as the amidated structure of the C-terminus, which are considered to be essential for their biologic activity. The human AM peptide has also been sequenced in pigs (Kitamura et al., 1994b), dogs (Ono et al., 1998), bovines (Kitamura et al., 2001), rats (Sakata et al., 1993) and mice (Okazaki et al., 1996) (Fig. 2). The amino acid sequence of human AM differs from porcine AM in 1 residue, from dog AM in 2 residues, and from bovine AM in 4 residues. Further, rat and mouse AM consist are 2 resides shorted than human AM and differs from human AM in 6 and 7 residues, respectively. As with the peptide superfamily, the 6 amino acids forming the disulphide bonded ring structure and the C-terminal 7 amino acids that contain the amidated C-terminal arginine are preserved. The precursor peptide of human AM consists of 185 amino acids, including a signal peptide of 21 amino acids (Kitamura et al., 1993b). Both ends of the mature 52 residue peptide adjoin the typical processing signals of lysine-arginine and argininearginine. Further, there is a 20-residue segment (proadrenomedullin N-terminal 20 peptide (PAMP)) located between the Nterminus of the AM precursor and the mature sequence of the AM protein that is removed during post-translational processing. The C-terminal amino acid of PAMP sequence is amidated by a consensus amidation signal (glycine-lysine-arginine) (Fig. 2)

Studies have demonstrated that PAMP can produce vasodilation, suppress the sympathetic nervous system, and inhibit aldosterone secretion (Kitamura et al., 1994c; Katoh et al., 1995; Shimosawa et al., 1995; Andreis et al., 1997a). 3. Structure and variation of the human adrenomedullin gene 3.1. Gene structure The cDNA sequence of the human AM gene was described by Kitamura et al. (1993b), and the gene was subsequently cloned and sequenced (Ishimitsu et al., 1994b). As illustrated in Fig. 3, the gene is composed of 4 exons interposed by 3 introns. Further, the entire nucleotide sequence corresponding to the 52 amino acid residues of the mature AM protein product is encoded by the fourth exon, while the 20 residues of the PAMP protein are encoded by portions of the second and third exons. The human AM gene is located at the distal end of the short arm of chromosome 11 (p15.1–3) (Fig. 3) (Ishimitsu et al., 1994b, 2001a, 2001b), close to the loci of several other known genes, including sphingomyelinase (p15.1–4), parathyroid hormone (p15.1–2) and lactate dehydrogenase (p14–15.1) (Li et al., 1988; Arnold et al., 1989; da Veiga Pereira et al., 1991). 3.2. Variation of the human adrenomedullin gene 3.2.1. Microsatellite DNA polymorphisms Human genomic DNA contains numerous microsatellite markers that consists of variable numbers of short nucleotide repeats and that can be utilized to localize the genomic region associated with hereditary diseases or traits (Heesom et al., 1997; Sharma et al., 1998; Rehemudula et al., 1999). Further, the number of nucleotide repeats within some microsatellite

CGRP

ACDTATCVTHRLAGLLSRSGGVVKNNF-VPTNVGSKA-F

amylin

KCNTATCATQRLANFLVHSSNNFGAIL-SSTNVGSNT-Y

intermedin

911

human AM

TQAQLLRVGCVLGTCQVQNLSHRLWQLMGPAGRQDSAPVDPSSPHSY N-terminal C-terminal 1 10 20 30 40 50 YRQSMNNFQGLRSFGCRFGTCTVQKLAHQIYQFTDKDKDNV-APRSKISPQGY

porcine AM

YRQSMNNFQGLRSFGCRFGTCTVQKLAHQIYQFTDKDKDGV-APRSKISPQGY

canine AM

YRQSMNNFQGPRSFGCRFGTCTVQKLAHQIYQFTDKDKDGV-APRSKISPQGY

bovine AM

YRQSLNNFQGLRSFGCRFGTCTVQKLAHQIYHFTDKDKDGS-APRSKISPQGY

rat AM

YRQSMN--QGSRSTGCRFGTCTMQKLAHQIYQFTDKDKDGM-APRNKISPQGY

mouse AM

YRQSMN--QGSRSNGCRFGTCTFQKLAHQIYQLTDKDKDGM-APRNKISPQGY

PAMP

ARLDVASEFRKKWNKWALSR

Fig. 2. Amino acid sequences and peptide structures of adrenomedullin (AM) and related peptides in various species. CGRP, calcitonin gene-related peptide; PAMP, proadrenomedullin N-terminal 20 peptide. The link between cysteines denotes disulfide bonding. The C-terminus of AM, CGRP and amylin peptides is amidated.

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T. Ishimitsu et al. / Pharmacology & Therapeutics 111 (2006) 909–927 15.5 15.4 15.3 15.2 15.1 14

AM gene 8.0 kb

1 kb 13

0.7kb

5.8 kb

12

EcoRI site

phage arm

11.22 11.21 11.1

phage arm Cytosine-Adenine repeat

3'

5'

1.8kb

+223A/C

+1100C/G

0.5 kb

11th chromosome

PAMP

AM

Fig. 3. Choromosomal sublocalization and genomic structure of the human adrenomedullin (AM) gene. Dotted areas in the exons are translated into the peptide, proadrenomedullin. The heavily hatched area corresponds to mature AM and the proadrenomedullin N-terminal 20 peptide (PAMP).

patients with end-stage renal disease (9.0%) (Ishimitsu et al., 2003) than in patients with coronary artery disease (2.3%), patients with type 2 diabetes without nephropathy, and healthy subjects. By contrast, the frequencies of 11-, 13- and 14-repeat alleles were not significantly different among healthy subjects and patients with coronary artery disease and diabetes mellitus. These findings suggest that the 19-cytosine-adenine-repeat allele of microsatellite DNA polymorphism adjacent to the human AM gene is associated with the genetic predisposition to essential hypertension and diabetic nephropathy in Japanese subjects, but not with coronary artery diseases or type 2 diabetes mellitus. However, the plasma AM levels do not vary with the number of microsatellite cytosine-adenine-repeats (Ishimitsu et al., 2001b). Therefore, it is unlikely that the global AM gene expression is affected by this microsatellite DNA polymorphism, and this microsatellite DNA polymorphism may be linked to variations in other nearby genes related to the cardiovascular system.

markers can affect the expression of associated genes (Shah et al., 1998; Nakayama et al., 2000a, 2000b). Nucleotide sequencing of genomic DNA around the human AM gene has identified a microsatellite marker with a variable number of cytosine-adenine repeats located 4 kb downstream from the 3′-end of the AM gene (Fig. 3) (Ishimitsu et al., 2001a). In the Japanese population, there are 4 types of alleles with different numbers (11, 13, 14 and 19) of cytosine-adenine repeats. The frequency of each allele in 300 normal healthy subjects is: 11 repeats, 28.8%; 13 repeats, 33.5%; 14 repeats, 34.7%; and 19 repeats, 3.0%. Fig. 4 shows the frequencies of these alleles in Japanese patients with essential hypertension (n = 143), coronary artery disease (n = 111), type 2 diabetes mellitus without nephropathy (n = 106) and end-stage renal disease due to type 2 diabetic nephropathy (n = 128). The frequency of the 19-cytosine-adenine-repeat allele was significantly higher (7.3%) in patients with essential hypertension (Ishimitsu et al., 2001b) and in patients with type 2 diabetic

Number of cytosine-adenine repeats 11

13

14

19

Healthy subjects

χ2=9.86 p<0.02

Essential hypertension Coronary artery disease Diabetes without nephropathy

χ2=17.2 p<0.001

Renal failure due to diabetic nephropathy Renal failure due to chronic glomerulonephritis

0

20

40

60

80

100

(%)

Fig. 4. The frequency distribution of 11-, 13-, 14- and 19- cytosine-adenine-repeat alleles of the microsatellite polymorphism adjacent to the human AM gene in healthy subjects, patients with essential hypertension, patients with coronary artery disease, type 2 diabetic patients without nephropathy, hemodialysis patients with type 2 diabetes mellitus and hemodialysis patients due to chronic glomerulonephritis.

T. Ishimitsu et al. / Pharmacology & Therapeutics 111 (2006) 909–927

3.2.2. Single nucleotide polymorphisms Human genomic DNA also exhibits thousands of single nucleotide changes, called single nucleotide polymorphisms, that can confer a genetic predisposition towards various cardiovascular disorders (Daley & Cargill, 2001). Even when the single nucleotide does not affect the sequence coding for the peptide product of the gene, it can affect gene expression by modulating the conformation of DNA or the binding of a transcription factor. The human AM gene possesses single nucleotide polymorphisms in intron 1 (+ 223A/C) and intron 3 (+ 1100C/G) that exist in linkage disequilibrium with each other (Ishimitsu et al., 2005). Most single nucleotide polymorphisms associated with cardiovascular disorders modulate expression of function of cardiovascular hormones or their downstream signal transduction elements. Therefore, investigation of the effect of single nucleotide polymorphisms on the expression and bioactivity of AM gene may help characterize the role of AM in cardiovascular disease. 4. Receptor and signal transduction The distribution of binding sites for AM has been comprehensively studied in rats (Owji et al., 1995; Juaneda et al., 2003). The largest expression of receptors was found in heart and lung followed by adrenal, kidney and the central nervous system. In humans, the vascular endothelium and gastrointestinal immune cells also exhibit specific receptors for AM (Hagner et al., 2002a, 2002b). AM exerts its biological activity through receptor complexes composed of the calcitonin receptor-like receptor (CL) and specific receptoractivity modifying proteins (RAMP) (McLatchie et al., 1998). CL is a 7 transmembrane spanning protein that belongs to the guanine triphosphate binding protein coupled receptor family (type B or class II) and that generates cyclic adenosine monophosphate (cAMP) by the activation of Gs and adenyl cyclase. The RAMP family has 3 single-transmembrane protein members, RAMP1, 2 and 3, that transport CL to the cell surface and determine the specificity and affinity of ligands. The combination of CL and RAMP1 forms the receptors that are specific for CGRP, and the CL combined with RAMP2 or RAMP3 comprises receptors for AM, termed AM1 and AM2 receptors, respectively (Poyner et al., 2002) (Fig. 5). The differential roles of these 2 AM receptors have not been fully clarified. Recent studies have reported that the C-terminus of RAMP3, but not that of RAMP2, contains tandem PSD95/Discs-large/ZO-1 homology domains that interact with Na+/H+ exchanger regulatory factor-1 and that inhibit the agonist-induced internalization of the receptor complex (Bomberger et al., 2005a, 2005b). These findings suggest that AM-1 and AM-2 receptors are subject to different regulatory mechanisms in terms of intracellular trafficking, which subsequently mediate desensitization and resensitization of receptor activities. Early studies suggested that cAMP is the primary second messenger that mediates AM action. However, as shown in Fig. 5, later studies reported that AM also increases the synthesis of

CGRP

CL

913 AM

RAMP1

RAMP2,3

CL Tyrosine kinase

Adenyl Cyclase cAMP

extracellular signal-regulated kinase

Protein kinase A

Phosphatidylinositol 3 kinase Akt NO synthase NO

Mitogenic action

Anti-proliferative

Fig. 5. Receptor composition and possible intracellular signal transduction scheme of adrenomedullin.

nitric oxide (NO) and thereby increases cyclic guanosine monophosphate (cGMP) (Hirata et al., 1995; Hayakawa et al., 1999). Further, NO synthase is enhanced by the activation of protein kinase A by cAMP. AM has also been shown to elicit phosphatidylinositol 3-kinase activation and Akt phosphorylation resulting in the stimulation of endothelial NO synthase (Nishimatsu et al., 2001). By contrast, another study reported that AM stimulated extracellular signal-regulated kinase via protein tyrosine kinase activation (Iwasaki et al., 1998) and may thereby modulate the mitogenic state of the cell. 5. Biological actions 5.1. Vascular action AM produces vasodilation in potencies that are comparable to CGRP. In anesthetized rats, bolus intravenous injection of AM rapidly elicits a decrease in total peripheral resistance, resulting in blood pressure reduction that persists for more than 10min (Kitamura et al., 1993a). Further, AM also induces vasodilation and an increase in blood flow in various regional vascular beds, including the cerebral, coronary, pulmonary and renal circulations (Lippton et al., 1994; Hirata et al., 1995; Lang et al., 1997; Yoshimoto et al., 1998). Similarly, in humans, intravenous infusion of AM elicits dose-dependent blood pressure reduction accompanied by a decrease in total peripheral resistance (Lainchbury et al., 1997, 2000; Nagaya et al., 2000a). This hypotensive effect of AM occurs at physiological plasma concentrations and causes minimal reflex activation of sympathetic nerves and the reninangiotensin-aldosterone system, suggesting that AM may directly inhibit these neuroendocrine systems (Lainchbury et al., 1997). The AM receptor is coupled with adenyl cyclase and vasodilator action of AM is chiefly mediated by cAMP generation. However, AM also stimulates NO synthase as shown in Fig. 5. Therefore, the increase in NO production may be the primary mechanism by which AM induces vasodilation. Indeed, the vasodilator action of AM can be attenuated by removal of endothelium or by administration of the NO synthase inhibitor (Feng et al., 1994; Hirata et al., 1995).

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5.2. Heart Systemic administration of AM increases cardiac output while simultaneously lowering blood pressure in healthy subjects and in patients with heart failure (Lainchbury et al., 2000; Nagaya et al., 2000a). This increase in cardiac output is produced by AM-mediated decreases in systemic blood pressure (i.e., cardiac afterload) and by coronary dilation and increase coronary flow (Parkes, 1995). Further, AM increases cAMP and activates protein kinase A, thereby increasing myocardial contractility (Ihara et al., 2000). AM has also been shown to exhibit positive inotropic effects on cardiac muscle by increasing intracellular calcium independent of cAMP (Szokodi et al., 1998). However, other investigators report that AMinduced increases in NO and cGMP results in negative inotropic effects in isolated rabbit cardiomyocytes (Ikenouchi et al., 1997). In addition, AM did not show positive or negative inotropic actions in experiments using human cardiac muscles (Saetrum Opgaard et al., 2000). Thus, the direct inotropic effect of AM on myocardium remains controversial, and the increased cardiac output in response to AM administration is likely primarily mediated by the dilation of coronary vascular beds and by reduction in afterload.

in normal humans (Lippton et al., 1994). Finally, investigators have reported that inhalation of AM inhibited bronchoconstriction induced by histamine or acetylcholine (Kanazawa et al., 1994). 5.5. Central nervous system Immunohistochemical, in situ hybridization and binding studies have demonstrated that AM and its receptors are widely distributed in the cerebral cortex, hypothalamus, medulla oblongata, spinal cord and the lining of the ventricles (Satoh et al., 1996; Sone et al., 1997; Serrano et al., 2000; Shan & Krukoff, 2001a; Stachniak et al., 2003). Investigators have reported that water deprivation reduces AM gene expression in the supraoptic and paraventricular nuclei of rat hypothalamus (Shan & Krukoff, 2001a) and that intracerebroventricular injection of AM causes suppression of water drinking and food intake (Murphy & Samson, 1995; Taylor et al., 1996). Thus, AM may act on the central nervous system to regulate homeostasis of body fluid and electrolyte balance. Other investigators have reported that central administration of AM results in increased blood pressure and heart rate via enhanced sympathetic outflow (Takahashi et al., 1994; Saita et al., 1998).

5.3. Kidney

5.6. Endocrine system

The mRNA for CL, RAMP2 and RAMP3 are expressed in the renal cortex and medulla of rats (Yoshihara et al., 2001). Further, immunohistochemical studies have shown that AM is present in the glomeruli, distal tubules and medullary collecting ducts (Jougasaki et al., 1995; Owada et al., 1997), which suggests that AM may modulate renal physiology. Indeed, vivo administration of AM produced a marked diuresis and natriuresis in experimental animals (Ebara et al., 1994; Jougasaki et al., 1995; Vari et al., 1996), possibly via increases in renal vasodilation and increased renal blood flow. However, low doses of AM increase urinary sodium excretion without affecting GFR in rats with heart failure (Nagaya et al., 1999). Alternatively, the renal vasodilator, diuretic, and natriuretic responses to AM may be mediated by the release of NO and prostaglandins (Majid et al., 1996; Jougasaki et al., 1997), but in vitro experiments in the distal tubule luminal membrane demonstrated that AM stimulated sodium uptake, rather than excretion (Leclerc & Brunette, 2000). Taken together, these data suggest that AM induces diuresis and natriuresis via increases in renal vasodilation and renal blood flow.

Studies investigating the effects of AM on the production and secretion of other hormones are summarized in Table 1. AM produces a wide variety of effect on the neuroendocrine system, particularly in relation to cardiovascular endocrine factors. While 2 studies have reported that PAMP inhibits the release of noradrenaline from adrenergic nerve endings (Shimosawa et al., 1995; Fujioka et al., 1999), other studies report conflicting results regarding the effect of AM on the cardiovascular endocrine systems (Table 1). Thus, AM may have different actions in different cell types and in different species. Regardless, most studies agree that AM suppresses the reninangiotensin-aldosterone system and the action of endothelin under different conditions.

5.4. Lung The lung also possesses abundant binding sites for AM (Owji et al., 1995; Juaneda et al., 2003). High levels of mRNA for CL and RAMP2 have been reported in lung tissue (Hay & Smith, 2001; Sexton et al., 2001). While AM produces vasodilation in pulmonary arteries and veins (Shirai et al., 1997), intravenous injection of AM induces a greater decrease in systemic blood pressure than in pulmonary arterial pressure

5.7. Mitogenesis and apoptosis AM inhibits the proliferation of cultured vascular smooth muscle cells, glomerular mesangial cells and cardiac fibroblasts (Chini et al., 1995; Kano et al., 1996; Segawa et al., 1996; Tsuruda et al., 1999), and this antimitogenic effect of AM may be mediated by cAMP-induced activation of protein kinase A. AM also exerts a mitogenic action in cultured mouse fibroblasts, human oral keratinocytes (Withers et al., 1996; Kapas et al., 1997) and in some types of tumor cells (Miller et al., 1996). This is consistent with observations that AM has multiple effects on the regulation of cell growth depending on the types of cells and the stage of the cell cycle (Shichiri et al., 2003). AM also inhibits apoptosis in cultured rat aortic endothelial cells (Kato et al., 1997), possibly by upregulating the gene expression of Max which subsequently binds to c-myc.

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915

Table 1 Effects of adrenomedullin on other endocrine factors Hormone

Effect

Experimental setting

Species

Author, year

Catecholamines

Increased Unchanged Increased Increased Decreased Decreased Decreased Decreased Decreased Decreased Increased Decreased Decreased Increased Increased Decreased Decreased Increased Decreased Decreased

Adrenal slices In vivo Isolated perfused kidney In vivo Isolated aorta Dispersed adrenal cells Dispersed adrenal cells Dispersed adrenal cells Dispersed pituitary cells In vivo In vivo (i.c.v.) In vivo (i.c.v.) Cultured cardiomyocytes In vivo In vivo Isolated aorta Cultured VSMC Isolated islets Isolated islets In vivo

Human Dog Rat Sheep, human Rat Rat Rat Rat Rat Sheep Rat Rat Rat Sheep Human Rat Rat Rat Rat Rat

Andreis et al., 1997b Masada et al., 1999 Jensen et al., 1997 Charles et al., 2003 Tian et al., 1995 Yamaguchi et al., 1996 Andreis et al., 1997a Mazzocchi et al., 1999 Samson et al., 1995 Parkes & May, 1995 Shan & Krukoff, 2001b Yokoi et al., 1996 Sato et al., 1997 Rademaker et al., 1997 Petrie et al., 2001 Tian et al., 1995 Kohno et al., 1995 Mulder et al., 1996 Martinez et al., 1996 Zudaire et al., 2003

Renin Angiotensin II Aldosterone

ACTH

Vasopressin ANP

Endothelin-1 Insulin

ACTH, adrenocorticotropic hormone; ANP, atrial natriuretic peptide; i.c.v., intracerebroventricular administration; VSMC, vascular smooth muscle cells.

Although c-myc is recognized as a key proto-oncogene, it can also promote apoptosis in the absence of serum or growth factors. Therefore, the increased heterodimerization of Max/cmyc induced by AM is expected to reduce apoptosis via modulation of c-myc (Shichiri et al., 1999). AM also inhibits apoptosis of human umbilical vein endothelial cells via a NOdependent but cGMP-independent mechanism (Sata et al., 2000). The anti-apoptotic effect of AM has been also demonstrated in other cell types, including cardiomyocytes, endometrial cancer cells and adrenal zona glomerulosa cells (Oehler et al., 2001; Albertin et al., 2003; Yin et al., 2004). Taken these together, these data suggest that AM modulates cardiovascular tissue by inhibiting apoptosis and inhibiting excessive cellular proliferation. 5.8. Anti-oxidation

SSRE (326) SSRE(375)

CAAT(–128) NF-IL6 (–93) TATA(–26)

CAAT(–628)

1 158

6. Regulation of production 6.1. Analysis of promoter activity Analysis of the 5′-flanking region of the genomic AM gene has yielded vital information regarding the regulation of the AM gene transcription. Fig. 6 shows the distribution of the consensus sequences of transcription factor binding sites. The 5′-flanking region of human AM gene contains TATA and

0.5 kb 628 875 1259 1448 1293 1565 606 726 1025

2303

AP-2(532,546)

CRE(347)

AP-2(–157,–166) AP-2 (–43,–55)

–500

AP-2 (–374)

AP-1(–922)

–1000

AP-1 (–1174)

–1500

HIF-1(–863) HIF-1(–825)

HIF-1 (–1203)

Administration of salt and angiotensin II produces oxidative stress in cardiovascular tissues and results in perivascular

inflammation of the coronary arteries in the heterozygotes of AM knock-out mice. These data suggest that endogenous AM protects against oxidative stress (Shimosawa et al., 2002). Indeed, this anti-oxidant effect of AM has been shown to be mediated by the cAMP/protein kinase A pathway (Yoshimoto et al., 2004). Further, AM-induced increases in NO and cGMP may reduce generation of reactive oxygen species by inhibiting nicotinamide-adenine dinucleotide phosphate oxidase (Kato et al., 2003).

cDNA

proAM

AM

Fig. 6. Distribution of consensus sequences for binding sites of transcription factors in the promoter region of the human adrenomedullin gene. AP-1, activator protein 1; AP-2, activator protein 2; HIF-1, hypoxia-inducible factor-1; CAAT, CAAT box; TATA, TATA box; NF-IL6, nuclear factor for interleukin-6 expression; SSRE, shear stress responsive element; CRE, cAMP responsive element.

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CAAT boxes at −26 and − 128 bases from the transcription start site, respectively, which is typical to the promoter structure of eukaryotic genes. The promoter also contains multiple binding sites for the activator protein-1 (AP-1) and activator protein-2 (AP-2). AP-1 is involved in the signal transduction from mitogen-activated protein kinases (MAPK) and oncogenes, such as jun and fos. By contrast, AP-2 is induced by the activation of phospholipase C and protein kinase C. The AM promoter also contains the binding consensus sequence for nuclear factor for interleukin-6 expression (NF-IL6) at − 85 to − 93 bases. This consensus sequence belongs to the CCAAT/ enhancer binding protein family and also exists in the promoter region of the genes for various acute-phase proteins, such as Creactive protein, haptoglobin and interleukin-6. Since AM stimulates cAMP production (Kitamura et al., 1993a), the cyclic adenosine monophosphate responsive element (CRE) at +347 base in the intron 1 likely mediates feedback signals from the target cells. Finally, the presence of multiple consensus sequences for shear stress responsive element (SSRE) and hypoxia-inducible factor-1 (HIF-1) suggests that mechanical stress and hypoxia may modulate transcription of the AM gene. Further analysis of these cis-acting elements may provide clues to the regulatory mechanisms underlying AM production. The mRNA of AM is present at relatively high levels in cardiovascular tissues, including fibroblasts, vascular endothelial cells and smooth muscle cells (Sugo et al., 1994a, 1994b; Tomoda et al., 2001). In fact, production of AM by the vascular cells throughout the body is the main source of circulating AM (Nishikimi et al., 1994). Based on the likely physiologic importance of this phenomenon, we performed extensive study of the promoter activity of the human AM gene in cultured human aortic endothelial cells (Ishimitsu et al., 1998). In these experiments, the 1.5 kb genomic DNA fragment corresponding to the promoter region of the AM gene was ligated to the luciferase reporter vector and transfected into cultured HAEC. When the length of the promoter region DNA was gradually shortened from the 5′-end, the gene expression activity was decreased by 41% in the absence of nucleotides − 93 to − 85, which correspond to the consensus sequence of the nuclear factor for NF-IL6 binding site (TGAGGAAAG). Further, gene expression activity was further decreased by 42% in the absence of nucleotides − 66 to − 29, which contain multiple binding sites for AP-2. Site-directed mutagenesis and electrophoretic mobility shift assays also indicated that 2 transcription factors, NFIL6 and AP-2, participate in the regulation of the human AM gene expression in vascular endothelial cells. 6.2. Factors regulating AM production 6.2.1. Inflammatory cytokines and nitric oxide Production of AM by cultured cells can be augmented by inteleukin-1 and tumor necrosis factor-α (Sugo et al., 1995a; Isumi et al., 1998). Further, plasma AM levels are markedly elevated in patients with infectious or inflammatory disorders (Hirata et al., 1996; Ishimitsu et al., 1999). NF-IL6 may partly mediate cytokine-induced increases in AM, as the promoter region of AM gene contains the binding consensus sequence for

NF-IL6 and because NF-IL6 is induced by interleukin-1, tumor necrosis factor-α and interleukin-6 (Akira et al., 1990). Further, NF-IL6 may serve as a transcription factor in the acute-phase reaction against inflammatory tissue injuries. Based on these data, NF-IL6 may induce AM, resulting is vasodilation and increased blood flow, and thereby facilitate delivery of leukocytes to inflamed tissues. Indeed, transgenic mice overexpressing AM are resistant to organ damage due to endotoxininduced shock (Shindo et al., 2000). Alternatively, NO promotes the expression of AM mRNA in vascular endothelial and smooth muscle cells and may also mediate the action of inflammatory cytokines (Hofbauer et al., 2002). 6.2.2. Hypoxia, ischemia and oxidative stress Various studies have demonstrated that hypoxia and ischemia induces AM expression (Ladoux & Frelin, 2000; Ogita et al., 2001; Sandner et al., 2004). One study demonstrated that this phenomenon could be mediated by the HIF-1 consensus binding site located at nucleotide positions − 770 and − 1095 of the mouse AM gene (Cormier-Regard et al., 1998). This mechanistic scheme may also be applicable to the regulation of human AM gene expression, because the 5′flanking region of the human AM gene also contains a HIF-1 consensus sequence at nucleotides − 825, − 863 and − 1203. Further, the endothelial per-aryl hydrocarbon nuclear receptor translocator-sim domain protein-1, which plays an important role in the gene expression induced by hypoxic stimuli, promotes AM gene expression via Src, a non-receptor tyrosine kinase, in cardiomyocytes (Tanaka et al., 2002). This pathway also mediates the signaling cascade induced by inflammatory stimuli, such as interleukin-1. Based on these data, increased AM may dilate blood vessels and thereby restore blood flow to ischemic tissue. This is supported by observations that AM expression is increased by focal ischemic injury in the rat brain cortex (Wang et al., 1995) and that AM in the coronary vessels is markedly increased by ischemia in the perfused rat heart (Belloni et al., 2004). Experimental and clinical studies have indicated that production of AM is also stimulated by reactive oxygen species (Ando et al., 1998; Chun et al., 2000; Saito et al., 2001; Katsuki et al., 2003). However, the cis-elements in the promoter region or the mechanism by which oxidative stress induces AM gene transcription have not yet been identified. 6.2.3. Mechanical stimuli Plasma AM levels are increased in patients with hypertension (Ishimitsu et al., 1994a; Kohno et al., 1996; Kato et al., 1999). Further, in vivo experiments in rats have demonstrated that acute pressure overload stimulates left ventricular AM gene expression (Romppanen et al., 1997), and ex vivo experiments using the isolated perfused rat heart showed that acute pressure loading increases AM gene expression in the left ventricle, while stretching of cultured neonatal ventricular myocytes resulted in inhibition of AM gene expression (Luodonpaa et al., 2003). By contrast, Tsuruda et al. reported that AM gene expression and secretion were induced by mechanical stretching in cultured rat cardiomyocytes (Tsuruda et al., 2000). Similar

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conflicting results have been reported regarding the effect of shear stress on AM expression in cultured endothelial cells (Chun et al., 1997; Shinoki et al., 1998). Namely, Chun et al. have reported that shear stress increased AM expression in cultured endothelial cells of the human umbilical vein, while Shinoki et al. reported that shear stress inhibited AM expression in HAEC. The reason for this discrepancy may be attributed to difference in the strength and duration of the stimulus or to differences in signal transduction pathways between arterial and venous endothelial cells. Regardless, the human gene possesses 2 consensus sequences for SSRE in intron 1 (Fig. 6), suggesting that AM gene transcription is influenced by physical and mechanical stimuli. 6.2.4. Renin-angiotensin system and the sympathetic nervous systems The renin-angiotensin system and the sympathetic nervous system play pivotal roles in the regulation of the cardiovascular system and in the pathophysiology of cardiovascular diseases. In vitro experiments using cultured cells indicated that angiotensin II and noradrenaline stimulate production of AM (Sugo et al., 1995b; Isumi et al., 1998), and in vivo experiments showed that angiotensin II induces a rapid increase in cardiac AM gene expression in rats (Hirano et al., 2002). Further, angiotensin I converting enzyme inhibition reduces cardiac AM gene expression in dogs with congestive heart failure (Jougasaki et al., 2001), and studies have demonstrated high plasma AM concentrations in patients with high-renin essential hypertension (Letizia et al., 2002). Stimulation of α1-adrenergic and type 1 angiotensin II receptors elicits activation of phospholipase C, production of diacylglycerol, activation of protein kinase C and induction of AP-2. Since the 5′-flanking region of the human AM gene contains multiple binding sites for AP-2 (Fig. 6), stimulation of AM gene expression by angiotensin II and catecholamines may be mediated by the AP-2 induction. This is supported by observations that phorbol ester, an activator of protein kinase C, induces AM gene expression in human monocytic leukemia cells and that the cis-acting region (− 70 to − 30) containing multiple AP-2 binding sites is necessary for this induction (Nakayama et al., 2000a, 2000b). While some studies have demonstrated that protein kinase C and Ca2+ /calmodulin signaling systems are involved in angiotensin II-induced AM secretion from rat cardiac myocytes (Tsuruda et al., 2001), other studies have suggested that a protein kinase other than protein kinase C is involved in the regulation of AM mRNA production by bovine aortic endothelial cells (Barker et al., 1998). Furthermore, Autelitano et al. reported that phorbol ester and protein kinase C activation inhibit AM gene expression in neonatal rat cardiomyocytes (Autelitano et al., 2001). Despite the discrepancies in results between these studies, it seems likely that AP-2 participates in the transcriptional regulation of the AM gene. 6.2.5. Other endocrine factors While AM stimulates cAMP production in various cells, other studies have demonstrated that AM gene expression is

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decreased by cAMP in various cultured cells, including vascular endothelial cells, smooth muscle cells, fibroblasts and adrenal chromaffin cells (Sugo et al., 1995b; Kobayashi et al., 1999; Tomoda et al., 2001). As shown in Fig. 6, a consensus sequence of CRE is located in intron 1 at the nucleotide position of + 347. This CRE may mediate feedback regulation from cAMP. Steroid hormones may also affect production of AM. For example, the mineralocorticoid, aldosterone, augments AM gene expression in cultured vascular endothelial cells and smooth muscle cells (Isumi et al., 1998; Uemura et al., 2002). Further, glucocorticoids, such as hydrocortisone and dexamethasone, have been shown to stimulate AM gene expression in fibroblasts, cardiomyocytes and vascular cells (Minamino et al., 1995; Isumi et al., 1998; Tomoda et al., 2001). However, dexamethasone inhibits cytokine-induced AM gene expression in human glioblastoma cells (Takahashi et al., 2003). In vivo and in vitro experiments have demonstrated that estrogen and its receptor are involved in the regulation of AM gene expression in the ovary and uterus (Cameron et al., 2002; Giacalone et al., 2003; Ikeda et al., 2004), but androgens do not appear to affect AM gene expression in prostate tissue (Jimenez et al., 2003). With regard to other endocrine factors, thyroid hormones, such as triiodothyronine, have been shown to promote AM gene expression in vascular cells and fibroblasts (Minamino et al., 1995; Isumi et al., 1998; Tomoda et al., 2001), and plasma AM concentrations are elevated in patients with hyperthyroidism (Taniyama et al., 1996). Further, patients with hyperparathyroidism have increased plasma AM and increase AM production in the parathyroid tissue (Letizia et al., 2003, 2004). While plasma AM levels are also elevated in patients with insulinoma (Letizia et al., 2001) and in the context of acute hyperinsulinemia in patients with type 2 diabetes (Katsuki et al., 2002), the effects of insulin on AM gene expression or AM production remain poorly understood. Finally, the effect of the potent vasoconstrictor, endothelin, on AM production may differ according to the type of cells being studied. For example, endothelin-1 has been shown to increase AM production in cultured vascular smooth muscle cells or cutaneous keratinocytes (Sugo et al., 1995b; Kapas & Farthing, 2001) but decrease AM production in cultured endothelial cells (Isumi et al., 1998). 6.2.6. Oncogenes and carcinogens The expression of the AM gene and the production of AM have been recognized in several tumor cells, such as neuroblastoma (Dotsch et al., 2000), ovarian cancer (Hata et al., 2000), prostate cancer (Rocchi et al., 2001) and intraocular and orbital tumors (Udono et al., 2000). AM induces expression of Max, which subsequently forms a heterodimer with c-myc, an oncogene product, and thereby inhibits apoptosis (Shichiri et al., 1999). Experiments in rat fibroblasts suggest that c-myc gene expression stimulates the transcription of the AM gene but accelerates the degradation of AM mRNA, resulting in a relatively modest increase in AM secretion (Ozawa et al., 2004). Further, the v-Myc oncoprotein represses AM gene expression in mouse fibroblasts, possibly via Myc-mediated repression of the initiator element in the promoter region of the mouse AM gene (Wang et al., 1999). While the promoter region of the

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Based on these data, a putative mechanism of transcriptional regulation of the AM gene is proposed in Fig. 7, whereby AM gene expression is induced in response to a wide range of noxious stimuli, and the responses of AM produce compensatory and protective responses.

Angiotensin II Phospholipase C

Hypertension

cAMP

Diacylglycerol

AM

CRE Protein kinase C

SSRE AM Gene NO Expression NF-IL6 AP-1 HIF-1 Mitogen-activated Cytokines protein kinases

Carcinogenesis

AP-2

Hypoxia Ischemia

7. Pathophysiologic implications and therapeutic possibilities

Inflammation

Fig. 7. Putative regulatory mechanism of adrenomedullin (AM) gene expression. AP-1, activator protein 1; AP-2, activator protein 2; CRE, cAMP responsive element; SSRE, shear stress responsive element; NF-IL6, nuclear factor for interleukin-6 expression; HIF-1, hypoxia-inducible factor-1.

human AM gene does not have the consensus sequence for initiator element, there are at least 2 binding sites for AP-1 in the 5′-flanking region (Fig. 6). Thus, it is possible that the oncogene products activate MAPK, such as c-Jun-NH2-terminal kinase and extracellular signal-regulated kinase, resulting in induction of AP-1 and modulation of AM gene transcription (Minden & Karin, 1997; Wisdom, 1999). AM exerts a wide range of effects on cell growth and apoptosis. For example, AM promotes growth and suppresses apoptosis in vascular endothelial cells and human cancer cells (Miller et al., 1996; Kato et al., 1997; Miyashita et al., 2003a, 2003b) but also inhibits proliferation and facilitates apoptosis of glomerular mesangial cells and vascular smooth muscle cells (Kano et al., 1996; Osajima et al., 1999; Parameswaran et al., 1999). Therefore, the production of AM by proliferating cells and tissues exert autocrine/paracrine effects on cellular proliferation or generation of tumors.

The biological effects of AM are generally protective and beneficial to the cells and tissues. Therefore, delivery of AM to the tissue by exogenous administration or augmentation of endogenous production may be a viable therapeutic strategy for various disorders. Although the half-life of intravenously infused AM is approximately 22min (Meeran et al., 1997), several clinical strategies, including gene therapy and cell transplantation therapy, have been employed to increase the utility of AM as a therapeutic agent. 7.1. Hypertension The ability of AM to produce vasodilation highlights its potential utility as an antihypertensive agent. As demonstrated in Fig. 8, plasma AM levels are increased in hypertensive patients especially when accompanied by organ injuries such as left ventricular hypertrophy (Ishimitsu et al., 1994a) and may act to counteract further rises in blood pressure. Indeed, intravenous infusion of AM lowers systemic blood pressure in patients with essential hypertension (Troughton et al., 2000). Although chronic AM infusion using an osmotic minipump has been shown to attenuate blood pressure elevation in various rat models of hypertension (Khan et al., 1997a, 1997b; Yoshihara et al., 2005), such a device is unlikely to be applicable for the long-term treatment of hypertensive patients.

Plasma Adrenomedullin (fmol/ml)

12

*** 10

* ** ***

8

p<0.05 normal p<0.01 vs.. subjects p<0.001

***

***

6

**

* 4

*

**

* SE

2

Hypertension

Renal Failure

A I N YH A II N YH A I II N YH A IV

YH

1.5-3 3-6 >6 Serum creatinine

N

II

O

W H O

W H

Normal

I

0

Heart Failure

Fig. 8. Plasma levels of adrenomedullin in patients with essential hypertension, chronic renal failure and heart failure. Serum creatinine values are expressed in mg/dL. WHO, World Health Organization; WHO I, hypertension without organ damage; WHO II, hypertension with organ damage; NYHA, New York Heart Association; NYHA I, Symptoms of heart failure with more than ordinary activity; NYHA II, Symptoms of heart failure with ordinary activity; NYHA III, Symptoms of heart failure with minimal activity; NYHA IV, Symptoms of heart failure at rest.

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The degradation of AM is inhibited and the actions of endogenous AM are augmented by the inhibition of neutral endopeptidase (Lisy et al., 1998). Indeed, the cardiovascular tissue AM content is negatively correlated with the neutral endopeptidase activity in tissues from spontaneously hypertensive rats (Jiang et al., 2004). In addition, neutral endopeptidase inhibitors augment the effects of various other depressor peptides, including kinins and natriuretic peptides. Therefore, neutral endopeptidase inhibitors may have potential for use as antihypertensive agents (Burnett, 1999). Indeed, omapatrilat is a dual inhibitor of neutral endopeptidase and angiotensin I converting enzyme that has been shown to be effective as an antihypertensive drug in spontaneously hypertensive rats (Burrell et al., 2000). A clinical trial using omapatrilat as an antihypertensive agent, the OCTAVE (Omapatrilat Cardiovascular Treatment Assessment Versus Enalapril) study, has already performed (Kostis et al., 2004) and suggests that it has promising antihypertensive effects with possibly favorable influences on the cardiovascular endocrine system. However, angioedema was a notable side effect of the drug (Zanchi et al., 2003).

Second, AM may alleviate the progression of heart failure by the mechanisms described above. Indeed, AM administration immediately after myocardial infarction has been shown to ameliorate the development of heart failure in rats (Nakamura et al., 2005). Third, AM may attenuate myocardial damage after ischemia and reperfusion via its antioxidant and antiapoptotic properties. This is supported by studies that have demonstrated that intravenous administration of AM reduces the infarct size in rats that have undergone myocardial ischemia and reperfusion (Okumura et al., 2004) and that AM gene delivery can reduce the infarct size and the occurrence of ventricular arrhythmia in rats subjected to coronary occlusion and reperfusion (Kato et al., 2003). Finally, AM may inhibit maladaptive remodeling of cardiac tissue via its antiapoptotic and antifibrotic effects. In experiments using cultured cells, AM inhibited hypertrophy of cardiomyocytes and proliferation of fibroblasts (Tsuruda et al., 1998, 1999). In vivo experimental studies have also demonstrated the beneficial effects of AM infusion on left ventricular remodeling after ischemia (Nakamura et al., 2002; Okumura et al., 2003). These findings suggest that AM administration to patients with myocardial infarction may improve outcomes.

7.2. Heart failure

7.4. Renal failure

Plasma AM rises with increasing severity of heart failure (Fig. 8) (Nishikimi et al., 1995) and may prevent progression of heart failure. Indeed, intravenous administration of AM increases cardiac output and reduces pulmonary wedge pressure with little effect on heart rate and blood pressure, thereby resulting in increases in urine volume and urinary Na excretion (Nagaya et al., 2000a). These beneficial effects may be mediated by decreased afterload due to peripheral vasodilation and by the possible inotropic action of AM. In animal experiments, chronic AM administration attenuates the progression of cardiac dysfunction and improves the prognosis in rats developing chronic heart failure (Nishikimi et al., 2003). Thus, systemic administration of AM may be an effective therapy for the management of heart failure in the acute phase, while pharmacological blockade of AM catabolism may be a possible strategy for the chronic treatment of heart failure. Many experimental and clinical studies have investigated the effects of vasopeptidase inhibitors in the treatment of heart failure. In fact, the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE) study reported that the incidence of death and hospitalization was 11% lower in patients treated with omapatrilat than in patients treated with enalapril group (Packer et al., 2002). Thus, vasopeptidase inhibitors may improve the outcomes of patients with heart failure (Trindade & Rouleau, 2001).

As shown in Fig. 8, plasma AM levels increase with advancing severity of renal failure (Ishimitsu et al., 1994a). In addition to its vasodilator and natriuretic actions, AM may exhibit anti-inflammatory, antiproliferative, antifibrotic and cytoprotective effects on the kidney (Chini et al., 1997; Parameswaran et al., 1999; Iwamoto et al., 2003; Huang et al., 2005) and thereby prevent progression of renal injury. Indeed, intravenously administered AM results in diuresis and natriuresis even in patients with chronic renal impairment (McGregor et al., 2001). Since AM also increases NO production and reduces oxidative stress (Nishimatsu et al., 2002), administration of AM may be useful in the management of acute renal failure due to ischemia, inflammation and nephrotoxic agents. Indeed, co-administration of AM and the endopeptidase inhibitor resulted in improved renal dysfunction in sheep with experimental heart failure despite falls in blood pressure (Rademaker et al., 2002). With regard to the progression of hypertensive renal injury, chronic infusion of AM exerts renoprotective effects in Dahl salt-sensitive rats (Nishikimi et al., 2002), and AM gene delivery using a plasmid vector attenuated renal damage in various hypertensive models of rats (Chao et al., 2001). We have observed that the AM gene expression is especially high in the renal tissue of patients with malignant nephrosclerosis. Immunohistological staining using anti-human AM showed that the AM immunoreactivity is prominent in the interstitial fibroblasts and infiltrated macrophages (Fig. 9). Thus, increased AM production may be protective against the process of fibrosis and inflammation of the sclerosing kidney. Strict control of blood pressure and inhibition of the renin-angiotensin system are important for the prevention of the progression of chronic renal disease, and AM administration may further improve outcomes in patients with renal disease.

7.3. Myocardial infarction Plasma AM levels increases in the early phase of acute myocardial infarction in proportion to the clinical severity (Yoshitomi et al., 1998) and may result in compensatory, protective effects via several mechanisms. First, AM produces coronary vasodilation and increases coronary blood flow.

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A

shown to reduce thickening of the pulmonary artery and attenuate right ventricular hypertrophy (Yoshihara et al., 1998). Inhalation of AM in aerosols exerts a bronchodilator effect, as mentioned above (Kanazawa et al., 1994), and repeated inhalation of AM reduces pulmonary vascular resistance and improves survival of monocrotaline rats (Nagaya et al., 2003a). In clinical studies of patients with pulmonary hypertension, AM inhalation improved pulmonary hemodynamics without affecting systemic blood pressure and heart rate (Nagaya et al., 2004). Thus, while the optimal protocol for AM inhalation therapy remains unclear, its long-term clinical benefits appear promising. 7.6. Gene therapy

B

Fig. 9. Biopsied renal tissue preparations of patients with malignant nephrosclerosis. (A) The adrenomedullin immunoreactivity is prominent in the interstitial fibroblasts. (B) The macrophages that have infiltrated into the interstitium show strong immunoreactivity against adrenomedullin.

7.5. Pulmonary hypertension AM is also a vasodilator in the pulmonary vascular bed (Shirai et al., 1997), and the lung has possesses abundant receptors for AM (Owji et al., 1995; Hay & Smith, 2001; Sexton et al., 2001; Juaneda et al., 2003). Plasma AM levels are increased in patients with pulmonary hypertension (Kakishita et al., 1999) and may be lower in pulmonary veins than in the pulmonary arteries (Yoshibayashi et al., 1997). Interestingly, the vasodilation effect of AM on the pulmonary artery is particularly prominent when the pulmonary artery pressure is increased (Lippton et al., 1994). A clinical study in patients with pulmonary hypertension showed that intravenous infusion of AM reduces pulmonary vascular resistance and increases cardiac index. However, AM seems to reduce systemic blood pressure rather than pulmonary artery pressure, and this may limit the systemic use of AM in the acute management of pulmonary hypertension (Nagaya et al., 2000b). By contrast, chronic infusion of AM in rats with monocrotaline-induced pulmonary hypertension has been

Because the short plasma half-life of AM limits its use as therapy by systemic infusion, investigators have turned to delivery of an AM gene as a strategy to extend the beneficial actions of AM. Indeed, AM gene delivery using a plasmid or adenoviral vector has been shown to attenuate development of hypertension and alleviate various organ injuries, such as cardiac hypertrophy and renal dysfunction, in rat models of hypertension (Chao et al., 2001). Further, viral AM gene delivery reduces the infarct size after myocardial ischemia and protects against ischemic injury after cerebral artery occlusion in rats (Kato et al., 2003; Xia et al., 2004). In rats with streptozotocin-induced diabetes, injection of the adenovirus harboring the human AM gene reduced the accumulation of glycogen in cardiomyocytes and alleviated the development of cardiac dysfunction (Dobrzynski et al., 2002). AM promotes proliferation of vascular endothelial cells but inhibits proliferation and migration of vascular smooth muscle cells (Horio et al., 1995; Kano et al., 1996; Miyashita et al., 2003a, 2003b), which makes AM an attractive candidate to modulate the vascular responses to injury. Indeed, viral AM gene delivery inhibits neointimal formation in rat arteries after cuff-injury or balloon angioplasty (Agata et al., 2003; Yamasaki et al., 2003). In addition, AM promotes vascular regeneration via the NO-dependent pathway (Abe et al., 2003) and by activation of the phosphatidylinositol 3-kinase/Akt pathway (Kim et al., 2003; Miyashita et al., 2003a, 2003b). This angiogenic effect of AM results in improvements in collateral vessel formation and blood flow in the ischemic limbs of rabbits after intramuscular administration of AM gene DNA conjugated with positively charged gelatin (Tokunaga et al., 2004). In order to enable the application of AM gene therapy in clinical practice, the efficiency and duration of AM gene expression must be optimized. Plasmid vectors driven by a potent promoter, such as the cytomegalovirus promoter, seems to offer a sufficient amount of gene expression, but the duration of action is insufficient for clinical application. Therefore, it is essential to exploit embedding material, such as liposome and gelatin, which enables longer and more stable gene expression. With regard to viral vectors, the duration of gene expression in produced by adenoviral vectors is limited. The alternative use of retroviral vectors, which infect dividing cells, enables a longer lasting gene expression. Nevertheless, further endeavors are

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needed in order to improve the properties of viral vectors to increase gene expression activity, lengthen the duration of gene expression while simultaneously minimizing injury of infected cells and minimizing the immune responses of the host. 7.7. Cell transplantation therapy Isolation of circulating endothelial progenitor cells has allowed development of autotransplantation of bone marrow cells as a therapeutic modality. Because AM promotes the proliferation and inhibits apoptosis of some cell lines, including vascular endothelial cells (Kato et al., 1997; Miyashita et al., 2003a, 2003b), it may promote the efficiency of cell transplantation therapy in several ways. First, AM may promote proliferation and survival of endothelial progenitor cells and thereby increase the number and potency of transplanted cells. Indeed, in vitro experiments have already demonstrated that AM can magnify the expansive response of hematopoietic stem cells of umbilical cord blood (De Angeli et al., 2004). Second, co-administration of AM may enhance the efficiency and effectiveness of cell transplantation therapy. For example, studies have demonstrated that subcutaneous infusion of AM enhances the therapeutic potency of stem cell transplantation in rats subjected to cerebral artery occlusion and in rats with hindlimb ischemia (Hanabusa et al., 2005; Iwase et al., 2005). Third, AM gene delivery to the transplantation cells may result in increased AM production in the tissue receiving the cell transplantation and the beneficial effects that accompany increased AM production. This is supported by studies that have demonstrated that transplantation of AM gene-transduced endothelial progenitor cells caused greater improvement in monocrotaline-induced pulmonary hypertension in rats (Nagaya et al., 2003a, 2003b). 8. Conclusions and future perspectives Since AM was first identified 10 years ago, studies have yielded a considerable amount of information regarding the structure, function and variation of the AM gene and the distribution, production and behavior of the peptide. This has, in turn, led to a greater understanding of the biologic actions of AM and its importance in the pathophysiologic response to a variety of diseases. Generally, AM exerts beneficial actions, including vasodilation, natriuresis, stimulation of NO production and inhibition of apoptosis, and AM is proposed to play protective roles against the noxious influences of hypertension, angiotensin II, aldosterone, endothelin, hypoxia and oxidative stress. Systemic infusion of AM seems to exert promising therapeutic effects in the management of acutephase disorders, such as myocardial infarction, heart failure and renal failure, resulting in the preservation of organ function and improvement of the prognosis. Further, augmentation of endogenous AM by modification of AM metabolism is likely the most practical approach for the treatment of chronic diseases, such as hypertension and arteriosclerosis. In addition, the angiogenic and cytoprotective properties of AM may provide benefit in the regeneration therapy of injured

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tissues and organs in the context of myocardial infarction and arteriosclerotic obliteration. Most of these therapeutic possibilities using AM have been investigated in experimental disease models. However, the practical use of AM in clinical medicine seems imminent. In the next decade, a number of clinical trials will be performed to explore the beneficial actions of AM and to establish the indications and the optimal protocols of AM therapy for various diseases. References Abe, M., Sata, M., Nishimatsu, H., Nagata, D., Suzuki, E., Terauchi, Y., et al. (2003). Adrenomedullin augments collateral development in response to acute ischemia. Biochem Biophys Res Commun 306, 10–15. Agata, J., Zhang, J. J., Chao, J., & Chao, L. (2003). Adrenomedullin gene delivery inhibits neointima formation in rat artery after balloon angioplasty. Regul Pept 112, 115–120. Akira, S., Isshiki, H., Sugita, T., Tanabe, O., Kinoshita, S., Nishio, Y., et al. (1990). A nuclear factor for IL-6 expression (NF-IL6) is a member of a C/ EBP family. EMBO J 9, 1897–1906. Albertin, G., Carraro, G., Parnigotto, P. P., Conconi, M. T., Ziolkowska, A., Malendowicz, L. K., et al. (2003). Human skin keratinocytes and fibroblasts express adrenomedullin and its receptors, and adrenomedullin enhances their growth in vitro by stimulating proliferation and inhibiting apoptosis. Int J Mol Med 11, 635–639. Ando, K., Ito, Y., Kumada, M., & Fujita, T. (1998). Oxidative stress increases adrenomedullin mRNA levels in cultured rat vascular smooth muscle cells. Hypertens Res 21, 187–191. Andreis, P. G., Mazzocchi, G., Rebuffat, P., & Nussdorfer, G. G. (1997a). Effects of adrenomedullin and proadrenomedullin N-terminal 20 peptide on rat zona glomerulosa cells. Life Sci 60, 1693–1697. Andreis, P. G., Neri, G., Prayer-Galetti, T., Rossi, G. P., Gottardo, G., Malendowicz, L. K., et al. (1997b). Effects of adrenomedullin on the human adrenal glands: an in vitro study. J Clin Endocrinol Metab 82, 1167–1170. Arnold, A., Kim, H. G., Gaz, R. D., Eddy, R. L., Fukushima, Y., Byers, M. G., et al. (1989). Molecular cloning and chromosomal mapping of DNA rearranged with the parathyroid hormone gene in a parathyroid adenoma. J Clin Invest 83, 2034–2040. Autelitano, D. J., Ridings, R., & Tang, F. (2001). Adrenomedullin is a regulated modulator of neonatal cardiomyocyte hypertrophy in vitro. Cardiovasc Res 51, 255–264. Barker, S., Wood, E., Clark, A. J., & Corder, R. (1998). Cloning of bovine preproadrenomedullin and inhibition of its basal expression in vascular endothelial cells by staurosporine. Life Sci 62, 1407–1415. Belloni, A. S., Guidolin, D., Ceretta, S., Bova, S., & Nussdorfer, G. G. (2004). Acute effect of ischemia on adrenomedullin immunoreactivity in the rat heart: an immunocytochemical study. Int J Mol Med 14, 71–73. Bomberger, J. M., Parameswaran, N., Hall, C. S., Aiyar, N., & Spielman, W. S. (2005a). Novel function for receptor activity-modifying proteins (RAMPs) in post-endocytic receptor trafficking. J Biol Chem 280, 9297–9307. Bomberger, J. M., Spielman, W. S., Hall, C. S., & Parameswaran, N. (2005b). RAMP isoform-specific regulation of adrenomedullin receptor trafficking by NHERF-1. J Biol Chem 280, 23926–23935. Burnett Jr., J. C. (1999). Vasopeptidase inhibition: a new concept in blood pressure management. J Hypertens Suppl 17, S37–S43. Burrell, L. M., Droogh, J., Man in't Veld, O., Rockell, M. D., Farina, N. K., & Johnston, C. I. (2000). Antihypertensive and antihypertrophic effects of omapatrilat in SHR. Am J Hypertens 13, 1110–1116. Cameron, V. A., Autelitano, D. J., Evans, J. J., Ellmers, L. J., Espiner, E. A., Nicholls, M. G., et al. (2002). Adrenomedullin expression in rat uterus is correlated with plasma estradiol. Am J Physiol 282, E139–E146. Chao, J., Kato, K., Zhang, J. J., Dobrzynski, E., Wang, C., Agata, J., et al. (2001). Human adrenomedullin gene delivery protects against cardiovascular remodeling and renal injury. Peptides 22, 1731–1737.

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