B: Therapeutic targets for heart failure

European Journal of Pharmacology 724 (2014) 1–8

Contents lists available at ScienceDirect

European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar

Review

Cardiac SERCA2A/B: Therapeutic targets for heart failure Mohammad Abrar Shareef a, Lucman A. Anwer a, Coralie Poizat b,c,n a b c

College of Medicine, AlFaisal University, Riyadh, Saudi Arabia Cardiovascular Research Program, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia San Diego State University, Department of Biology, 5500 Campanile Drive, San Diego, CA 92182, USA

art ic l e i nf o

a b s t r a c t

Article history: Received 8 September 2013 Received in revised form 10 December 2013 Accepted 11 December 2013 Available online 18 December 2013

Calcium (Ca2 þ ) recycling is key for effective relaxation of the cardiac muscle. Failure to properly recycle calcium through the sarcoplasmic reticulum (SR) results in severe impairment of myocardial relaxation and consequently alteration of the “beat-to-beat” heart rhythm and contractile function. The Sarco(Endo) plasmic reticulum Ca2 þ ATPase (SERCA) is instrumental for recycling cytosolic Ca2 þ into the lumen of the SR. Among the many SERCA isoforms identified so far, SERCA2a is restricted to slow-twitch skeletal and cardiac muscle, while SERCA2b is ubiquitously expressed. SERCA2a/b expression and activity are altered in major heart diseases such as ischemic heart disease, cardiomyopathies and congestive heart failure. Restoring adequate SERCA2a/b expression by pharmacological action or gene delivery has emerged as a new approach for the treatment of heart failure. In this review we describe the drugs adopted in clinical practice that activate SERCA2a/b function as well as new promising therapeutic tools using SERCA2 viral gene delivery to improve cardiac function and treat heart failure. & 2013 Elsevier B.V. All rights reserved.

Keywords: Sarco/endoplasmic reticulum Ca2 þ -ATPase SERCA2a/b Heart failure Calcium

Contents 1. 2.

3. 4.

5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 SERCA2a and SERCA2b isoforms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 2.1. Expression of SERCA2a and SERCA2b . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 2.2. Function of SERCA2a and SERCA2b. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 SERCA2a/b and cardiac diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Drugs targeting SERCA2a and SERCA2b . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 4.1. Drugs affecting expression of SERCA2a and SERCA2b . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 4.1.1. Up-regulation of SERCA2a and SERCA2b . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 4.1.2. Down-regulation of SERCA2a and SERCA2b . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 4.2. Drugs affecting the function of SERCA2a and SERCA2b . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 4.2.1. Increased function of SERCA2a and SERCA2b . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 4.2.2. Decreased function of SERCA2a and SERCA2b . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Gene therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 5.1. Methods for gene delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 5.1.1. Antegrade arterial infusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 5.1.2. Retrograde venous infusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 5.1.3. Direct intramyocardial injection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 5.1.4. Aortic cross clamping . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 5.1.5. Pericardial injection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 5.1.6. Intravenous infusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

n Correspondence to: Cardiovascular Research Program, King Faisal Specialist Hospital & Research Centre, PO Box 3354, Riyadh 11211, Kingdom of Saudi Arabia. Tel.: þ 966 1 464 7272x32984; fax: þ966 1 4427858. E-mail address: [email protected] (C. Poizat).

0014-2999/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejphar.2013.12.018

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5.2. Clinical 6. Conclusion . . . Funding . . . . . . . . . References . . . . . . .

trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........................................................................................................ ........................................................................................................ ........................................................................................................

1. Introduction The contraction and relaxation of cardiac muscle is associated with Ca2 þ movements. During depolarization, Ca2 þ moves into the cytosol through voltage gated calcium channels (Bers, 2002). This rise in intra-cellular Ca2 þ further induces Ca2 þ release from the sarcoplasmic reticulum (SR), which triggers Ca2 þ binding to troponin C resulting in contraction of the cardiac muscle (Tobacman, 1996). Removal of Ca2 þ from the cytosol to the SR induces relaxation of the muscle (Bassani et al., 1994; Bers, 2002; Vangheluwe et al., 2006) (for reviews). Cytosolic Ca2 þ removal is achieved by the action of several pumps including the Na þ /Ca2 þ exchanger (NCX) (Philipson et al., 2002), the plasma membrane Ca2 þ ATPase (PMCA) (Shull, 2000; Verboomen et al., 1994), as well as the secretory pathway Ca2 þ / Mn2 þ -ATPases (SPCAs) (Wuytack et al., 2002). However, the most effective mechanism and optimal control of Ca2 þ homeostasis is the re-storage of Ca2 þ back into the SR by the Sarco(Endo)plasmic Reticulum Ca2 þ ATPase named SERCA (Periasamy and Huke, 2001). Increased SERCA activity generates a 1000 fold of Ca2 þ concentration gradient across the sarcoplasmic reticular membrane (Frank et al., 2003) resulting in the restoration of approximately 70% of cytosolic Ca2 þ into the SR lumen during the relaxation of the cardiac muscle in rabbit and human (Bassani et al., 1994; Vangheluwe et al., 2006). SERCA proteins are expressed mainly as 3 isoforms, SERCA1, 2, and 3. SERCA1 is further expressed as two types, SERCA1a and b; SERCA1a is located in fast skeletal muscles in the adult, while SERCA1b is found on fast skeletal muscle during the fetal and neonatal life (Brandl et al., 1987). SERCA2 is the most widely distributed protein of the SERCA group and has 3 isoforms; 2a, 2b, and 2c (Vangheluwe et al., 2005). While SERCA2a is expressed on slow-twitch skeletal muscles and on cardiac myocytes, SERCA2b is detected in a variety of tissues (Wuytack et al., 1998). SERCA2c expression was originally detected in epithelial and endothelial cell linings but some reports also document its expression in cardiomyocytes (Gelebart et al., 2003). SERCA isoforms expressed in the normal and in the diseased myocardium have been reviewed recently (Dally et al., 2010). Several regulatory proteins modulate the activity of the SERCA2 pumps. Sarcolipin (SLN) for instance is mainly localized in the atrium, and inhibits the expression of both SERCA1a and SERCA2b (Asahi et al., 2003; Odermatt et al., 1998). Phospholamban (PLB), a membrane protein highly expressed in ventricular muscle critical for heart contractility, suppresses the function of SERCA protein (Simmerman and Jones, 1998). The regulation of cardiac contractility by SERCA2a binding partners has been described in a recent review article (Kranias and Hajjar, 2012) and will therefore not be covered here. In this review we summarize advances in the treatment of heart failure by increasing SERCA2a/b expression through pharmacological action or by the more recent viral-mediated gene delivery system.

2. SERCA2a and SERCA2b isoforms SERCA2a and SERCA2b are encoded by the ATP2A2 gene in human and Atp2a2 in mice. The 30 end of ATP2A2 encompasses 8 exons that after alternative splicing generate four SERCA2 mRNA

6 6 6 6

transcripts. The first one encodes for SERCA2a, while the other three encode for SERCA2b (Van Den Bosch et al., 1997; Ver Heyen et al., 2001). SERCA2 proteins are similar in size and include a catalytic portion and 10 transmembrane segments. The c-terminal end of SERCA2 differs in both SERCA2a and b isoforms. In SERCA2a, it is made of 4 amino acids (tetrapeptide tail), while in SERCA2b it is composed of 49 amino acid residues (Campbell et al., 1992, 1991; Lytton and MacLennan, 1988). The C-terminus of SERCA2a is located in the cytoplasm, while that of SERCA2b is exposed to the lumen of the sarco(endo)plasmic reticulum (Campbell et al., 1991; Vangheluwe et al., 2006). 2.1. Expression of SERCA2a and SERCA2b SERCA2a is expressed in slow-twitch skeletal and cardiac muscle. SERCA2b is present in smooth muscle cells and also in non-muscle tissue thus referred to as the “housekeeping” isoform (Campbell et al., 1991). In the heart, SERCA2a is predominantly expressed over SERCA2b (Lompre et al., 1994; Periasamy et al., 2008). Both isoforms differ in their location; while SERCA2b is concentrated around the T-tubules of SR, SERCA2a is distributed close to the T-tubules and longitudinally and transversely in the SR throughout the cardiac myocytes (Greene et al., 2000). 2.2. Function of SERCA2a and SERCA2b To transfer Ca2 þ ions into the SR, SERCA2 proteins utilize two specialized domains: E1 and E2 (see Fig. 1). E1 has a high affinity for Ca2 þ and its binding site is exposed towards the sarcoplasm, while E2 has a lower affinity for Ca2 þ and is hanging towards the lumen of the SR. Once the cardiomyocytes relax, Ca2 þ ions are released from Troponin C and bind to the binding site of E1 (aspartic acid residue) (Clarke et al., 1989, 1990; MacLennan et al., 1992), preceded by the binding of ATP (Wuytack et al., 2002). This Ca2 þ –E1–ATP complex is phosphorylated to form a high-energy phospho-intermediate. Conformational changes convert the phospho-intermediate into an ADP-insensitive phospho-enzyme intermediate. This results in the redirection of the Ca2 þ binding site towards the lumen of the SR. Since this form has a lower affinity for the Ca2 þ , Ca2 þ ions dissociate from the complex and get dispersed into the SR lumen followed by the release of inorganic phosphate molecule. Once the optimum restorage of the Ca2 þ occurs in the SR, E2 undergoes conformational changes in its structure and becomes E1 (Wuytack et al., 2002). There are functional differences between SERCA2a and SERCA2b. For instance, SERCA2b has two times higher affinity for Ca2 þ and two fold lower catalytic turnover rate compared to SERCA2a (Lytton et al., 1992; Verboomen et al., 1994). This phenomenon can be explained by several mechanisms; first, the last 12 amino acids of SERCA2b interact with several transmembrane segments (M1þM2þM3þM4þM7þ M8þM9þM10) causing stabilization of SERCA2b in E1 form with increased affinity for Ca2þ , thus reducing its overall activity (Campbell et al., 1991; Frank et al., 2003; Verboomen et al., 1994). Second, the rate of dephosphorylation of SERCA2b is three times lower than SERCA2a. This decreased rate of dephosphorylation reduces the rate of calcium ion removal, thereby reducing its activity. Third, the transition of 2Ca2þ –E1–P into 2Ca2þ –E2–P is two fold slower in SERCA2b than SERCA2a (Dode et al., 2003; Vandecaetsbeek et al., 2009).

M.A. Shareef et al. / European Journal of Pharmacology 724 (2014) 1–8

3

Fig. 1. Ca2 þ recycling during contraction–relaxation cycle in the cardiac muscle. Note the cyclic changes that occur for SERCA2 in order to deliver Ca2 þ from the cytosol into the lumen of the SR against the concentration gradient hydrolyzing one ATP molecule for each 2 Ca2 þ in diastolic phase of the cardiomyocyte.

Table 1 List of drugs that alter cardiac SERCA2a/b expression and function. SERCA2a/b expression ↑

SERCA2a/b function ↓

↑

↓

Name

Reference

Name

Reference

Name

Reference

Name

Reference

Enalapril

Guo et al. (2003)

Doxorubicin

Etomoxir

Greene et al. (2000)

Nifekalant

Losartan

Guo et al. (2003)

Nifekalant

Arai et al. (2000) Endo et al. 2006) Takeshita et al. (2008) Ryall et al. (2008) Zima et al. (2008) Prasad and Inesi (2011)

Enalapril

Guo et al. (2003)

Formoterol

Losartan

Guo et al. (2003)

Amitriptyline

Carvedilol

Koitabashi et al. (2005) Xu et al. (2008)

Verapamil

Endo et al. (2006) Ryall et al. (2008) Zima et al. (2008) Wang et al. (1984) Wang et al. (1984) Wang et al. (1984)

Carvedilol

Koitabashi et al. (2005) Phenylephrine Anwar et al. (2005)

Isoproterenol

Candesartan

Soga et al. (2006)

Amitriptyline

Insulin-like growth factor I Astragaloside IV

Byrne et al. (2009)

Cyclosporine

Xu et al. (2008)

Glucocorticoids De et al. (2011)

Metoprolol Resveratrol Hydralazine Oxymatrine

Formoterol

Bridges et al. (2005), Kubo et al. (2001) Sulaiman et al. (2010) Kao et al. (2011) Gwathmey et al. (2011)

Astragaloside IV

Diltiazem

Ivabradine

Maczewski and Mackiewicz (2008)

Nisoldipine

Istaroxime

Khan et al. (2009), Micheletti et al. (2007) Hughes et al. (2010)

Felodipine

Wang et al. (1984)

Thapsigargin (TG)

Kao et al. (2011)

Cyclopiazonic Acid (CPA)

Gwathmey et al. (2011) Pearl et al. (2011)

2,5-di(tert-butyl)hydroquinone (DBHQ) 1,3-dibromo-2,4,6-tris (methylisothio-uronium) benzene (Br2TITU)

Rasmussen et al. (1978) Seidler et al. (1989) Inesi et al. (2005) Berman and Karlish (2003)

Heparin-derived oligosaccharides Hydralazine Oxymatrine Glucocorticoids

3. SERCA2a/b and cardiac diseases Calcium is central for the coupling of excitation–contraction. Changes in Ca2 þ homeostasis after partial depletion of SR Ca2þ ,

impairment of Ca2þ channels, Ca2þ leaks or reduced expression of SERCA2 occur in major cardiac diseases including ischemic heart disease, hypertrophic and dilated cardiomyopathies, which often progress to heart failure. Although alteration of SERCA2 expression

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and function may not always be the initial cause of heart disease, it clearly contributes to the deterioration of cardiac function after injury (Hasenfuss et al., 1997). Reduced SERCA2 expression and function were observed in ischemic cardiac muscle (Lee et al., 1967; Talukder et al., 2009; Toba et al., 1978; Zucchi et al., 1996), in hypertrophic heart (Arai et al., 1994; de la Bastie et al., 1990; Lamers and Stinis, 1979) and in dilated cardiomyopathy (Limas et al., 1987; Meyer et al., 1995). In spite of the majority of reports documenting that reduction in SERCA2 expression and function is associated with a variety of cardiac diseases, there is also evidence that chronic up-regulation of SERCA2 leads to cardiac hypertrophy and congestive heart failure (Vangheluwe et al., 2006). This emphasizes that reduced Ca2 þ uptake is not universally linked to heart failure. Genetically modified mice with altered cardiac SERCA2a/b expression show striking effects on cardiac function. Transgenic mice overexpressing SERCA2 in their heart exhibit accelerated contraction– relaxation cycles associated with enhanced calcium transients (He et al., 1997; Yao et al., 1998). Genetic ablation of the SERCA2 gene is embryonic lethal for homozygous mice (Periasamy et al., 1999) while heterozygous animals are viable and show reduced SERCA2 expression with reduced myocyte contractility and SR Ca2 þ load. Although heterozygous mice show no phenotype at baseline, they are hypersensitive to pressure overload and quickly develop heart failure (Schultz Jel et al., 2004). Inducible cardiac-specific deletion of SERCA2 in adult mice severely reduces both systolic and diastolic function seven weeks after gene excision. However, four weeks after gene ablation, SERCA2 protein are severely depleted in knockout mice but these mice display a moderate impairment of cardiac function, suggesting SR-independent Ca2 þ mechanisms that can compensate for SERCA2 depletion (Andersson et al., 2009). As such, the use of therapeutic approaches that increase SERCA2 expression or function has been suggested as effective strategies to alleviate the loss of contractile function that develops with heart failure.

4. Drugs targeting SERCA2a and SERCA2b Over the past 12 years, several drugs have been tested and were shown to modulate SERCA2a/b expression and function. Drugs that prevent the reduction or assist in restoring SERCA2a/b expression or activity are considered as good potential therapeutic tools to improve Ca2 þ homeostasis. On the other hand, drugs that reduce SERCA2a/b expression are expected to have additional adverse effects on cardiac function. Below we describe several commonly used drugs that affect SERCA2a/b. These drugs can be divided into two groups; those which affect SERCA2a/b expression and those which modulate its function (Table 1).

Carvedilol, a non-selective β-adrenoreceptor blocker and an α-receptor antagonist, not only attenuates hydrogen peroxideinduced decrease in SERCA2 protein and gene, but also significantly up-regulates SERCA2 gene expression. This suggests that Carvedilol is involved specifically in restoring SERCA2 gene transcription. The effect of Carvedilol on SERCA2 gene transcription is mediated by two important pathways; the Sp1- and Sp3transcriptional factor pathways (Koitabashi et al., 2005). Similarly, Metoprolol, a β1-receptor antagonist, restores SERCA expression in a rat heart model post myocardial infarction (Sun et al., 2005) and in humans (Kubo et al., 2001) and improves cardiac function after myocardial infarction (Kubo et al., 2001; Maczewski and Mackiewicz, 2008; Sun et al., 2005). The selective α-1 adrenergic agonist Phenylephrine induces a transient increase in SERCA2 mRNA and protein expression in adult rat cardiomyocytes. This effect is independent of protein kinase C (PKC) activation but requires activation of the calcineurin/nuclear factor of activated T cells (NFAT) pathway (Anwar et al., 2005). Administration of insulin-like growth factor I (IGF-1), a hormone released under the effect of growth hormone (GH) and given to patients with GH/IGF-1 deficiency (Cittadini et al., 1994) increases SERCA2a protein expression via activation of the P13 kinase-AktSERCA2a signaling pathway in adult rats (Kim et al., 2008). Resveratrol, a natural antioxidant agent used in a variety of diseases including heart diseases (Hung et al., 2000) restores SERCA2a protein by activating silent information regulator 1 (SIRT1) in chronic type 1 adult diabetic mice (Sulaiman et al., 2010). Components extracted from several plants used in traditional Chinese medicine exert their cardioprotective effects by increasing SERCA2 expression. This is the case of Astragaloside IV, a glycoside prepared by isolating saponin from Astragalus membrane; its protective effect restores SERCA2a expression in rats with Isoproterenol induced cardiac injury (Xu et al., 2008). Likewise, Oxymatrine, another Chinese drug used as anti-inflammatory agent, increased SERCA2a protein expression in isolated rat cardiomyocytes after induction of chronic heart failure (Hu et al., 2011). Hydralazine, a vasodilator that activates β1 and β2 adrenoreceptors, enhances SERCA2a mRNA and protein expression by decreasing methylation of the SERCA2a promoter. Also, administration of Hydralazine in rats with Isoproterenol-induced heart failure increases SERCA2a mRNA and protein expression (Kao et al., 2011). Glucocorticoids, which are commonly used in therapy to prevent cardiac dysfunction post cardiopulmonary bypass (CPB) (Schroeder et al., 2003), can also restore SERCA2a protein expression in CPB induced ischemic cardiomyocytes in piglets (Pearl et al., 2011). Additionally, BIIB-723, a Na þ /H þ exchanger inhibitor (NHE1 inhibitor), can ameliorate isoproterenol-induced downregulation of SERCA2a protein in rat hearts (Shibata et al., 2011).

4.1. Drugs affecting expression of SERCA2a and SERCA2b 4.1.1. Up-regulation of SERCA2a and SERCA2b In the past ten years, a number of drugs that increase SERCA2 expression have been tested in various animal models of heart failure. Some have shown promising results towards restoring the loss of contractile function occurring in heart failure. For instance, Enalapril, an angiotensin-converting enzyme inhibitor (ACEI), and Losartan, an angiotensin II receptor antagonist partially prevent SERCA2 protein down-regulation and left ventricular function reduction in a rat model of congestive heart failure (Guo et al., 2003). This effect on SERCA2 expression is mediated by the blockade of the renin-angiotensin system (Guo et al., 2003). Candesartan, another angiotensin II receptor blocker, can restore SERCA2 gene and protein expression in Daunorubicin-induced cardiomyopathy in rats. This improves cardiac function and suggests a potential protective role of SERCA2 in Daunorubicin-induced cardiotoxicity (Soga et al., 2006).

4.1.2. Down-regulation of SERCA2a and SERCA2b Contrary to drugs that up-regulate SERCA2 expression, there are drugs that reduce its expression, and these are mostly associated with impaired contractile function. Doxorubicin, a potent anti-neoplastic agent with known cardiotoxicity, reduces SERCA2 gene expression in rats. Down-regulation of SERCA2 mRNA transcript by Doxorubicin is attributed to several mechanisms; increased H2O2production, increased binding of the transcription factor Egr-1 to the SERCA2 gene, which inhibits SERCA gene transcription, and activation of p44/p42 mitogen-activated protein kinase (p44/42 MAPK) pathway (Arai et al., 2000). Recently, the immuno-suppressive drug cyclosporine A that disturbs calcineurin/NFAT pathway, was shown to suppress SERCA2 protein expression in rat cardiac muscles (Prasad and Inesi, 2011). Isoproterenol, a non-selective β-adrenergic agonist, reduces SERCA2 expression (Takeshita et al., 2008). Chronic administration

M.A. Shareef et al. / European Journal of Pharmacology 724 (2014) 1–8

of the β2-adrenoceptor agonist Formoterol in rat cardiomyocytes also reduces SERCA2 gene and protein levels (Ryall et al., 2008). Nifekalant, a class III antiarrhythmic agent, when infused in failing rat hearts decreases SERCA2 protein expression (Endo et al., 2006). Amitriptyline, a tricyclic antidepressant agent, minimizes SERCA2 protein expression in ventricular myocytes of cats and rabbits suggesting its cardiotoxic role (Zima et al., 2008). Furthermore, excessive glucocorticoids reduce SERCA2a, one of the mechanisms by which ventricular dysfunction manifests as one of side effects of glucocorticoids (De et al., 2011).

4.2. Drugs affecting the function of SERCA2a and SERCA2b 4.2.1. Increased function of SERCA2a and SERCA2b Besides drugs that affect SERCA2 expression, there are drugs that cause an improvement in SERCA2 function primarily by increasing the pump activity. Etoximir, an inhibitor of cellular fatty acid metabolism, improves SR function by increasing the rate of SR Ca2 þ uptake (Rupp and Vetter, 2000). Similarly, Enalapril and Losartan, two drugs that have been previously discussed, improve SR function and cardiomyocyte Ca2 þ -handling abnormalities in rats with artificially induced congestive heart failure (Guo et al., 2003). Carvedilol, discussed also in the previous section, increases SERCA2 expression and improves SERCA2 activity through modulating Sp-1 and Sp-3 pathways in H2O2 treated cardiomyocytes (Koitabashi et al., 2005). Similarly, Ivabradine restores SERCA2 function in rat hearts post-myocardial infarction (Maczewski and Mackiewicz, 2008). Istaroxime, an agent exerting inotropic effects by inhibiting Na þ -K þ ATPase, also causes up-regulation in the function of SERCA2 in human heart muscles (Khan et al., 2009; Micheletti et al., 2007). This drug is currently enrolled in a phase IIb clinical trial for treating chronic heart failure patients (Ghali et al., 2007). Astragaloside IV, a drug made from plant extracts used in traditional Chinese therapy attenuates the decrease in SERCA function in isoproterenol-induced rat cardiomyocyte injury (Xu et al., 2008). Similarly, Oxymatrine, an alkaloid compound also enriched in traditional Chinese herb with many beneficial effects, increases SERCA2a function in rat cardiomyocytes with chronic heart failure (Hu et al., 2011). Recently, the anti-hypertensive drug Hydralazine was shown to increase SERCA2a function by decreasing the promoter methylation of SERCA2a in isoproterenol-induced heart failure in rat hearts (Kao et al., 2011). Likewise, heparin-derived oligosaccharides increase SERCA2 activity by interacting with the cytoplasmic domain of phospholamban (Hughes et al., 2010). Moreover, the previously discussed group glucocorticoids have the ability to prevent additional deterioration in SERCA2a protein activity in CPB induced ischemic cardiac muscles in piglets (Pearl et al., 2011).

5

In addition to the various drugs, there are several chemical inhibitors of the SERCA2A protein, such as Thapsigargin (TG), Cyclopiazonic Acid (CPA), 2,5-di(tert-butyl)hydroquinone (DBHQ) and 1,3dibromo-2,4,6-tris (methyl-isothio-uronium) benzene (Br2-TITU). Thapsigargin, the most widely studied inhibitor of all, is a sesquiterpene lactone derived from a plant source (Rasmussen et al., 1978). It forms a dead end complex with the ATPase stabilizing it in the ground E2 state. Likewise, DBHQ has a similar but weaker action on the ATPase pump; stabilizes the enzyme in the ground state through a distinct point of attachment (Inesi et al., 2005), thereby preventing calcium bonding and phosphoenzyme formation. Another highly selective inhibitor, Cyclopiazonic Acid, is a mycotoxin synthesized by some strains of Penicilin cycolpium and Aspergillus flavus. Unlike TG, which forms a dead end complex by decreasing ATP, CPA hinders ATPase activity by decreasing its affinity to bind ATP only (Seidler et al., 1989); hence it is a weaker inhibitor than TG (Plenge-Tellechea et al., 1997). Last in the list and the most recently studied inhibitors of all is Br2-TITU (Berman and Karlish, 2003). Unlike TG and DBHQ, it inhibits ATPase activity by interfering with the kinetics E1P–2Ca2 þ to E2P transition (Inesi et al., 2005).

5. Gene therapy Despite significant advances with the use of pharmacological drugs such as inotropic agents in the treatment of heart failure, the use of these drugs remains controversial mostly due to their pleiotropic effects. Recently, gene therapy has received increasing attention as a targeted delivery approach to reverse depressed contractile function. SERCA2a viral-mediated gene transfer used in animal models and in human failing cardiomyocytes has shown some beneficial effects on cardiac performances. Among the many vector systems examined so far, recombinant viral vectors have the highest gene transfer efficiency and are associated with an increased long-term transgenic expression (Tilemann et al., 2012). Among them, adenoviral vectors (AV) and adeno-associated viral vectors (AAV) are the most commonly used vectors in cardiac diseases (Gwathmey et al., 2011). Despite the ease with which adenoviral vectors can be produced (Isner, 2002), they have many limitations including the development of neutralizing antibodies that can disrupt the vector transferred. The most significant concern with AV vectors is the intensive induction of immune reaction that they induce, which has severely impacted their use in clinical settings. On the other hand, AAV do not induce such a strong immune response and carry the capacity for long term transgenic expression, making them superior to AV in clinical gene transfer for the treatment of cardiovascular diseases (Gwathmey et al., 2011; Tilemann et al., 2012). 5.1. Methods for gene delivery

4.2.2. Decreased function of SERCA2a and SERCA2b Drugs that decrease the function of SERCA2 include Nifekalant, an antiarrhythmic agent which inhibits SERCA2 activity and decreases the rate of calcium reuptake by the SR of the cardiac myocytes (Endo et al., 2006). Similarly, the β2-agonist Formoterol causes a decline in SERCA2 activity in cardiac myocytes (Ryall et al., 2008). Amitriptyline, a tricyclic antidepressant used to treat many conditions including tension headaches and anxiety disorders, reduces SERCA2 protein function in ventricular myocytes (Zima et al., 2008). A group of calcium channel blockers including Verapamil, Diltiazem, Nisoldipine and Felodipine suppress SERCA2 activity in dog cardiac muscles (Wang et al., 1984).

For a gene delivery method to be efficient, it must have high transduction efficiency, cover a large area of cardiac muscle and target specific molecular pathology. Literature has revealed various in vivo methods that have been used in small and large animals, each of which has distinct transduction efficiencies, advantages and limitations (Gwathmey et al., 2011). These methods have been described in details in (Tilemann et al., 2012) and a summary description of each one is given below. 5.1.1. Antegrade arterial infusion To date antegrade coronary artery infusion is considered to be the safest percutaneous gene delivery method, but has a lower efficiency compared to other delivery methods. To overcome this

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reduced efficiency many optimization methods have been developed such as the coronary venous blockade and the V-Focus system; which is a novel perfusion technique that establishes an isolated perfusion of the regional myocardium (Beeri et al., 2010; Byrne et al., 2009; Hayase et al., 2005; Kaye et al., 2007). However, all these optimization studies pose some risk of potential damage to the myocardium, thereby limiting their clinical application. 5.1.2. Retrograde venous infusion Another route for the percutaneous delivery of therapeutic agents to the myocardium is the retrograde venous infusion (Karagueuzian et al., 1986; Ryden et al., 1991). Despite being an effective and minimally invasive procedure, retrograde venous infusion is a fairly complex approach and requires careful pressure monitoring and a specific set of expertise to be performed safely. 5.1.3. Direct intramyocardial injection It is one of the most widely used gene transfer methods. The main advantage of using this method is the high resultant local concentration of the vector because of the endothelial bypass. Additionally by keeping vector-blood exposure to a minimum level it prevents deactivation of the vector by circulating DNAses and allows for minimal distribution of vector to other non-target organs (Bish et al., 2008; Grossman et al., 2002). 5.1.4. Aortic cross clamping This is another method of gene delivery to the myocardium. It involves a vector being injected into the aortic root while the pulmonary artery and aorta are clamped for a few beats (Hajjar et al., 1998). Despite giving good results in rodents and piglets, the invasive nature and concomitant risk of morbidity of this approach has limited its translation into clinical studies on human subjects (Bridges et al., 2005; Davidson et al., 2001). 5.1.5. Pericardial injection In small animal such as rodents the vector can be delivered surgically (Fromes et al., 1999) while for bigger animals a percutaneous approach is usable. The pericardial delivery technique shows low transduction efficiency that can be improved via coadministration of proteolytic enzymes. However, this delivery method can disturb pericardial layers and is mainly used for large animals (Guzman et al., 1993). 5.1.6. Intravenous infusion This is the simplest and least invasive amongst the current available methods of cardiac gene delivery. An example of such a method is the injection of gene vector into the tail vein of rodents, which results in successful cardiac gene expression (Zincarelli et al., 2008). However, due to its limited cardiac specificity its usage is limited only to small animals. 5.2. Clinical trials The first clinical trial of SERCA2a gene therapy in humans; the CUPID trial was conducted to examine the effect of restoring SERCA2a expression in heart failure patients via AAV1-SERCA2a. Results of this first phase at 6 months revealed an improvement of left ventricular function with a good safety profile. The second phase of the trial enrolled around 39 advanced heart failure patients in which the intracoronary rAAV1 method was used as a mode of SERCA2a gene delivery. Results of this trial showed an improvement in cardiac biomarkers (NT-proBNP levels) and no further deterioration in New York Heart Association (NYHA) class of the AAV1-SERCA2a treated group versus the placebo. Furthermore, left ventricular end systolic volumes improved and the

frequency of cardiovascular events declined in the treated group compared to the placebo. The safety profile was decent and no disease related events, arrhythmias or abnormal lab results have been reported so far. The CUPID trial further reported that SERCA2a is considered a crucial target in heart failure (Hajjar et al., 2008; Jaski et al., 2009).

6. Conclusion The expression and function of SERCA2a/b is altered in multiple heart diseases such as myocardial ischemia, cardiac hypertrophy, dilated cardiomyopathy and congestive heart failure. Restoring this aberration is considered a promising strategy in cardiac dysfunction management. However, up until now, we have not developed a method to completely restore this pump dysfunction; the numerous drugs used thus far have only managed to slow down disease progression. The more recent development of SERCA2a gene delivery using safe and potent viral vectors does raise spirits; improvements in clinical events were reported in patients with heart failure 12 months and more recently 3 years after intracoronary infusion of AAV1/SERCA2A (Zsebo et al., 2013). Despite promising results of the 3-year CUPID study, results of long-term clinical gene therapy will be needed to conclude that AAV1/SERCA2A offers a safe novel therapeutic strategy for the treatment of human heart failure.

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