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Fibulins and Their Role in Cardiovascular Biology and Disease
CHAPTER SEVEN
Fibulins and Their Role in Cardiovascular Biology and Disease Claudia Cangemi*, Maria Lyck Hansen*, William Scott Argraves†,w, Lars Melholt Rasmussen*,1 *Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark † Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina, USA 1 Corresponding author: e-mail address: [email protected]
Contents 1. Introduction 2. Genes, Expression and Biochemistry 3. Genetically Modified Animals 4. Expression of Fibulins in Heart and Vasculature During Development 5. Fibulins in Arterial Disease 6. Fibulins and Heart Disease 7. Circulating Fibulins 8. Fibulins and Hemostasis 9. Fibulins and Possible Mechanism of Regulation 10. Conclusions and Perspectives References
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Abstract Fibulins are a group of extracellular matrix proteins of which many are present in high amounts in the cardiovascular system. They share common biochemical properties and are often found in relation to basement membranes or elastic fibers. Observations in humans with specific mutations in fibulin genes, together with results from genetically engineered mice and data from human cardiovascular tissue suggest that the fibulin family of proteins play important functional roles in the cardiovascular system. Moreover, fibulin-1 circulates in high concentrations in plasma and may function as a cardiovascular disease marker.
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Deceased.
Advances in Clinical Chemistry, Volume 67 ISSN 0065-2423 http://dx.doi.org/10.1016/bs.acc.2014.09.008
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2014 Elsevier Inc. All rights reserved.
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ABBREVIATIONS ADAMTS-1 a disintegrin and metalloproteinase with thrombospondin motifs-1 AFLI atrial fibrillation AS aortic stenosis AT1 angiotensin II type 1 cb calcium binding E embryonic day ECM extracellular matrix EGF epidermal growth factor fbln fibulin, mouse gene FBLN fibulin, human gene GPS giant platelet syndromes MI myocardial infarction MR mitral regurgitation MYH9 myosin, heavy chain 9, nonmuscle, human gene SMC smooth muscle cells T2DM type 2 diabetes mellitus TAA thoracic aortic aneurysm TAD thoracic aortic dissection TGF-β transforming growth factor-beta WT wild type
1. INTRODUCTION Fibulins are a family of eight extracellular matrix (ECM) glycoproteins, fibulin-1 to -8, characterized by a modular structure: they have epidermal growth factor (EGF)-like modules followed by calcium-binding (cb)-EGF-like modules, and they all contain a unique fibulin C-terminal domain (Table 1). Fibulin-1 and -2 constitute the subgroup of the “long fibulins”; they are larger and have an extra domain with anaphylatoxin units. These long fibulins were the first to be discovered in the beginning of the 1990s [1,2] and are capable of forming dimers [3–5]. Fibulin-3, -4, -5, and -7 belong to the second subgroup of the “short fibulins.” The short fibulins show similarities in structure and exist as monomers [6]. Fibulin-6 and -8 are also known as the “hemicentins” (hemicentin-1 and -2, respectively) and have aminoterminal von Willebrand domains followed by a long module of tandem immunoglobulin repeats [7,8]. The fibulins, although sharing similarities in terms of biochemical structures and location, have quite different functions and binding partners.
Table 1 Structure, chromosome localization, and expression of the fibulins in the cardiovascular system Name
Long fibulins
Short fibulins
Hemicentin
Structure
Size
Chromosome
Heart
Artery
Plasma
Fibulin-1 BM-90
90–100 kDa
22q13.31
✓
✓
✓
Fibulin-2
195 kDa
3p24–p25
✓
✓
✓
Fibulin-3 S1-5, T16, or EFEMP1
50 kDa
2p16
Fibulin-4 MBP1 or EFEMP2 UPH1, H411
50 kDa
11q13
✓
✓
✓
Fibulin-5 EVEC or DANCE UP50
65 kDa
14q32.1
✓
✓
Fibulin-7 TM14
48 kDa
2q13
Fibulin-6 Hemicentin-1
600 kDa
1q25.3
Fibulin-8 Hemicentin-2
600 kDa
9q34.11
FIB, fibulin module; EGF, epidermal growth factor-like domain; Cb-EGF, calcium-binding EGF; Mod. Cb-EGF, modified Cb-EGF; Inc. Cb-EGF, incomplete Cb-EGF; As, anaphylatoxin-like domain; Su, Sushi domain; vW, von Willebrand motif; Igs, immunoglobulin-like domain; TSPs, thrombospondin-1 motif; NID, nidogen-like domain.
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Fibulin-1, -2, -4, and -5 have been described in relation to the cardiovascular system in both healthy and pathological conditions and will therefore be the main focus of this chapter.
2. GENES, EXPRESSION AND BIOCHEMISTRY Fibulin-1 (FBLN-1; and also known as BM-90) was discovered by Argraves and coworkers in 1989 [1]. The gene for fibulin-1 was mapped on the long arm of human chromosome 22 (22q13.3) [9]. Fibulin-1 is a cb 90 kDa protein expressed in the ECM in many organs, often in relation to basement membranes, but it is also a plasma protein in blood having been shown to interact with fibrinogen [10,11]. Fibulin-1 has been shown to interact with integrins and versican [12], pointing toward a role in cell adhesion and mobility, while the ability of interacting with ADAMTS-1 (a disintegrin and metalloproteinase with thrombospondin motifs-1) [13] and nidogen [14] may suggest a role in matrix remodeling. Fibulin-1 has four alternative splicing variants: fibulin-1A, -1B, -1C, and -1D. They differ in their terminal fibulin domain in both length and amino acid sequence. At least fibulin-1C and -1D have been shown to have a different kind of interaction partner in the ECM [4,15], implying possible diverse functions of the different isoforms [16,17]. Fibulin-2 was discovered from sequence analysis of cDNA clones obtained from a mouse fibroblast library by Pan et al. in 1993 [2]. This fibulin showed 43% identity compared to fibulin-1 differing mainly in the first domain characterized by three anaphylatoxin-related segments. The fibulin-2 gene was localized by in situ hybridization to the p24–p25 region of human chromosome 3 and to the band D–E of mouse chromosome 6 [18]. Under physiological conditions, fibulin-2 is found in dimers consisting of two 195 kDa units covalently bonded [5]. Fibulin-2 is more often colocalized with fibulin-1, and it is also involved in matrix remodeling and cell motility. These two fibulins display a similar, but not entirely overlapping, repertoire of ECM protein-binding partners, and some animal studies indicate that fibulin-1 may compensate for the lack of fibulin-2 regarding some functions (further described in Section 3). Furthermore, fibulin-2 has also been shown to have a role in elastogenesis and to interact with type IV collagen [19].
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Table 2 General functions of fibulin-1, -2, -4, and -5 Function Fibulins involved
Cell adhesion and mobility
Fibulin-1 Fibulin-5
Matrix remodeling
Fibulin-1 Fibulin-2
Elastogenesis
Fibulin-2 Fibulin-4 Fibulin-5
The gene for fibulin-4, also known as EFEMP2 (EGF-containing fibulin-like ECM protein 2), has been located in chromosome 11 at 11q13.1 [20]. Fibulin-4 mRNA has been shown to be widely expressed in various tissues throughout the body and in particular at high levels in the vasculature [21]. This 50 kDa protein has a crucial role in elastogenesis through its binding capacity to tropoelastin and lysyl oxidase [22]. Fibulin-5, also known as EVEC or DANCE, is a 54 kDa integrinbinding ECM protein that mediates endothelial cell adhesion and, through its calcium-dependent elastin binding, has an essential function in the organization of elastic fibers [23]. The gene coding fibulin-5 is located at 14q31 [24]. The main functions of fibulin-1, -2, -4, and -5 are summarized in Table 2.
3. GENETICALLY MODIFIED ANIMALS Several animal knockout studies have been carried out since the discovery of fibulins to unravel their biological role of these proteins in vivo. The fibulin-1-deficient mice die perinatally suffering from impaired endothelial function of small blood vessels and severe defects in the basement membranes of many organs, including the kidneys and lungs resulting in fatal hemorrhaging and organ malformations [25]. Thus, no adult animals have been available for further studies. Fibulin-1 is essential during embryonic development since it is required for directing the migration and survival of cranial neural crest cell [26]. The development of
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pharyngeal glands, craniofacial skeleton, cranial nerves, aortic arch arteries, cardiac outflow tract, and cephalic blood vessels is dependent on a proper migration of the neural crest during embryo development. Thus, fibulin-1 is essential for the proper development of the vascular system, the kidneys, and the lungs. In the embryonic heart, fibulin-1 regulates versican-dependent events in ventricular morphogenesis by promoting ADAMTS-1 cleavage of versican leading to suppression of trabecular cardiomyocyte proliferation [27]. Fibulin-2 null mice develop normally and are phenotypically identical to their wild-type (WT) littermates. The function of fibulin-2 in embryonic development is probably dispensed in the mouse by functional redundancy with fibulin-1 [28]. In adult mice, fibulin-2 has been shown to play an important role in cardiac remodeling after experimentally induced myocardial infarction (MI). The knockout animals had less ventricular dysfunctions and hypertrophy and a better overall survival than the WT [29]. The reduced ventricular remodeling of the fibulin-2 null mouse is due to inhibition of the angiotensin II-induced TGF-β (transforming growth factorbeta) cardiac remodeling [30]. Disruption of fibulin-4 in mouse caused perinatal lethality due to elastic structures abnormalities at several organs, despite the normal amounts of tropoelastin [31]. The embryonic phenotype of the fbln4/ homozygous was characterized by narrow descending aorta and aorta tortuosity. Hanada et al. [32] generated later a mouse with reduced expression of fibulin-4 (fbln4R/R). This had quite a severe cardiovascular phenotype including vascular tortuosity, dilated ascending aorta, and increased heart size. Furthermore, a number of phenotypes, including loose skin and emphysema, typical of abnormal elastic fibers assembly, were described. The phenotype of fbln4R/R mouse resembles that typical phenotype of human connective tissue disorders such as Marfan syndrome. fbln4R/R mice develop severe aneurysm formation and aortic stiffening, followed by aortic dissection later in life. Fibulin-5 is responsible for the elastic fibers organization (polymerization of elastin). Fibulin-5-null mice exhibit lung and vasculature malformations [23,33]. The aorta of fibulin-5 null mouse is tortuous, elongated, and has disrupted elastic laminae, this defect being more severe in the outer lamina compared to the internal lamina [33]. However, these deficiencies are distinct from those resulting from fibulin-1 and -4 inactivation, suggesting that fibulin-1, -4 and -5 share structural but not functional redundancy during development. As well as fbln4R/R, fibulin-5 (fbln-5)-deficient mice were characterized by tortuous aorta with loss of compliance and a profound
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elastinopathy of the skin. Moreover, the fibulin-5 null mice show a significant increase of systolic blood pressure and pulse pressure compared to the WT. However, fibulin-5-deficient mice do not develop aneurysms, indicating that probably fibulin-4 is directly involved in the development of the pathology through TGF-β signaling.
4. EXPRESSION OF FIBULINS IN HEART AND VASCULATURE DURING DEVELOPMENT During cardiogenesis, fibulin-1 and -2 are present at high levels at sites of epithelial–mesenchymal transformation, endocardial cushion, and coronary vessels [34,35]. Fibulin-1 is also present in high amounts in the embryonic myocardium [36]. Fibulin-1, in particular, regulates versican-dependent events during ventricular morphogenesis [27]. Both fibulins are also present in the vessels with highest concentration in the adventitial area [37]. During embryonic development, fibulin-1 and -2 are also present at other locations such as the neural crest and the developing cartilage, tooth, and hair follicles [38], fibulin-2 expression being less prominent than fibulin-1 [38]. The high expression of fibulin-1 and -2 in the embryo is transient in most of the tissues and disappears during development. In the adult stage, fibulin-1 and -2 are present in the arterial walls and in the cardiac valves [34]. Fibulin-4 starts to be expressed in mouse embryo before the embryonic day (E) 14.5, and it is primarily involved in elastic fibers formation and then crucial for the development of the cardiovascular system [31]. The data regarding fibulin-4 expression during development are poor and mainly extrapolated from the knockout studies. Fibulin-5 is expressed in mouse embryos from E10.5 and its level becomes higher in the developing medial layer and endothelial cells of the latter-stage embryo E16.5 [39]. Moreover, fibulin-2 and -5 are both essential for the elastic laminae formation during postnatal development. Fibulin-2 is located in the subendothelial matrix of the blood vessels, while fibulin-5 is present throughout the whole vessel wall [40]. In the adult mice, fibulin-5 expression is attenuated and remains detectable only in the myometrial arteries, which are characterized by continuous angiogenesis. Although, fibulin-5 can be reactivated in adult blood vessels in response to injury [41]. Thus, fibulin-5 has its main role in embryonic vasculature formation, especially of the large vessels, in those processes involving fast smooth muscle and endothelial cell growth; later in life its activity is mainly related to vascular remodeling.
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In human, fibulin-4 and -5 are detectable in developing semilunar valve cushions as early as week 4 of gestation. Gene expression analyses showed significantly decreasing fibulin-4 levels in adolescent and in adult leaflets when compared with first- and second-trimester tissues; whereas fibulin-5 expression remained constant throughout the lifetime [42]. No information about fibulin-4 and -5 expression during human development in other organs is available to our knowledge.
5. FIBULINS IN ARTERIAL DISEASE The ECM has central importance for the blood vessels, in both physiological and pathological conditions, because not only it determines their mechanic characteristics but also it is involved in essential cellular activities such as migration and proliferation of smooth muscle cells (SMCs) and endothelial cells. The fibulins, as components of the ECM, have been shown to play an active role in these processes. Fibulin-1 is present throughout the arterial wall but its expression is higher in the outermost layer of the tunica media in association with the external elastic lamina (Fig. 1). Fibulin-1 has been associated with vascular calcification processes in mouse. Vascular calcification is a common clinical
Figure 1 Fibulin-1 and elastin in arterial wall. Shown is a cross-section of internal mammary artery stained using antifibulin-1 antibodies (A) and elastin Verhoeff staining (B). The Verhoeff stains elastin black. Most antifibulin-1 staining is in the tunica adventitia (A) with some staining at the media layer (M) close to elastic fibers and in the tunica intima (I).
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complication of diabetes and renal diseases, as it is characterized by osteoblastic transformation of the vascular SMCs. A microarray study showed that fibulin-1 was fourfold upregulated in mineralizing mouse vascular SMC [43]. Also, fibulin-1 has been shown to be a component of coronary artery atherosclerotic lesions in human [11]. In the lesions, fibulin-1 immunostaining colocalizes with fibrinogen staining [11], but the pathological mechanisms beyond are yet to be determined. Moreover, fibulin-1 expression appears to be related to arterial stiffness in human arteries. In a genomic study by Durier and coworkers [44], fibulin-1 gene expression was higher in human aorta from patients with increase arterial stiffness than in those with distensible aorta. Furthermore, fibulin-1 has been recently identified as the most upregulated transcript in nonatherosclerotic arterial tissue from patients with type 2 diabetes mellitus (T2DM) [45]. The prevalence of thoracic aortic aneurysm (TAA) is lower in patients with T2DM, and they have a decreased risk of progression and rupture of abdominal aortic aneurysms [46]. These indications altogether may suggest that the balance in expression of fibulin-1 is essential for a correct functioning of the vasculature and that this protein has an active role in vessels homeostasis. Fibulin-1 upregulation is associated with arterial stiffness and probably fibrotic elements in the vessels, as it is seen in diabetic arteriopathy; while its downregulation is connected to aortic dissection and increase in inflammatory responses. In healthy vasculature, fibulin-2 is present around the internal elastic lamina [47] and binds to versican, creating a network that interact with hyaluronan [48]. In mouse, fibulin-2 is present in vascular lesions, both atherosclerotic lesions and those induced by a periadventitial collar, and its expression appears to orchestrate the SMC response to injury. In particular, fibulin-2 upregulation in these lesions leads to enhanced SMC migration during repair mechanisms [49]. In estradiol-treated monkeys, fibulin-2 has been found highly expressed in atherosclerotic regions of the iliac artery, possibly because of its role in the lesion repair mechanisms [50]. Fibulin-2 was absent in regions with macrophages, thus it does not appear to be involved in the inflammatory processes. In aortic tissue of patients with aortic Stanford type A dissection and acute aortic dissection, fibulin-1 and -2 expression were downregulated [51,52]. Aortic dissection can be due to both inherited connective tissue disorders and acquired conditions such as chronic hypertension. A common characteristic in the etiology of aortic dissection is that the ECM undergoes accelerated degradation, apoptosis, and elastolysis leading to SMC necrosis
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and fibrosis of the elastic fibers. The significance of the connection of fibulin-1 and -2 to these remains to be made clear. Reduced expression of fibulin-4 in mouse leads to formation of aneurysms and aortic dissection due to elastic lamina disruption and cardiac abnormalities. The abnormalities in the vessel wall are due to both an aberrant deposition of elastin characterized by granular appearance in outer lamina and a disarray of the elastic fibers and matrix accumulation in the inner layers [32] and abnormal SMCs phenotype because of a reduced expression of contractile protein [53]. Fibulin-4-deficient mice have tortuous and elongated aortas with dilatation of the ascending tract, and they also have significantly higher pulse pressure compared to the WT probably due the aortic insufficiency [32]. In humans, fibulin-4 mutations were found in cutis laxa type I (autosomal recessive) patients; these individuals are characterized by a modest skin phenotype (inelastic skin) and predominant cardiovascular phenotype characterized by aortic aneurysms and arterial tortuosity and stenosis [54]. In addition to what has been shown by the animal studies, fibulin-4 impairment is also associated with TGF-β upregulation through Smad2 phosphorylation in human [54]. A novel mutation of fibulin-4 has recently been described in a cohort of Indian infants with lethal arteriopathy syndrome [55] underlining the importance of fibulin-4 in human elastogenesis. Furthermore, fibulin-4 expression was found to be decreased in the aortic wall of patients operated for acute and chronic ascending aortic dissection [56]. Fibulin-5 has a role as an inhibitor of SMCs proliferation and migration, and deletion of this protein causes abnormal vascular remodeling. Ligated carotid artery of fibulin-5-deficient mice showed increased vessel diameter and increased neointimal formation compared to WT. The carotid artery of these mice was also less elastic. Cultured vascular SMCs, isolated from fibulin-5-deficient mice, have enhanced proliferative and migratory response to mitogenic stimuli [57]; this was suppressed by overexpression of fibulin-5. In human, fibulin-5 has been found upregulated in the later stage of induced neointimal lesions and in the endothelial layer of atherosclerotic plaques [39,58]. Thus, fibulin-5 has a protective role orchestrating SMC turnover in physiological conditions and regulating SMC proliferation in response to injuries. At the same time, fibulin-5 contributes to the mechanic stability of the vessels through its interaction with elastin. Fibulin-5 is downregulated in the aortic wall of patients with thoracic aortic dissection (TAD). TAD is also characterized by degeneration and fragmentation of elastin in the arterial wall, which is probably due to fibulin-5
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reduction [59]. In addition, fibulin-5 was found to be downregulated in patients with calcified thoracic aneurysm in a recent proteomic study [60].
6. FIBULINS AND HEART DISEASE The fibulins in the heart are of central importance in several mechanisms behind the pathological changes. There are many evidences that link fibulin-1 to valvular heart pathologies, atrial fibrillation (AFLI), and cardiac impairment in general. Mitral regurgitation (MR) is a valvular heart disease that occurs when the mitral valve does not close properly during the systolic phase. This condition causes left ventricular remodeling through enhanced turnover of essential noncollagen ECM components. In a dog model of MR, a global decrease of the expression of ECM genes has been reported. In this study, fibulin-1 was almost twofold downregulated in MR [61]. Interestingly, also TGF-β was downregulated at the same degree suggesting a possible downstream effect on the synthesis of the ECM components. A pathway analysis of the dysregulated genes in the dog MR model identified a network of involved genes similar to the ones being influenced in the Marfan syndrome, MI, and aneurysm formation. Furthermore, fibulin-1 expression in atrial tissue of patients with AFLI was found downregulated by proteomics approach [62] (the study had though some limitations due to the small population size). Moreover, in a microarray study, fibulin-1 mRNA appeared to be upregulated in myocardial specimens from patients with coronary artery disease and patients with dilated cardiomyopathy compared to those from a nondiseased heart [63]. Loss of fibulin-2 in mouse protects against cardiac rupture and ventricular dysfunction and improved survival after MI [29]. Absence of fibulin-2 decreased the inflammatory response and collagen I and III deposition after MI reducing therefore ventricular remodeling. This could be attributed to the reduced upregulation of TGF-β signaling and other ECM proteins after MI of the fibulin-2-deficient mice compared to WT. Also, the reduction of the TGF-β signaling has been shown to attenuate angiotensin II-induced cardiac hypertrophy in the fibulin-2-deficient animals compared to the WT [30]. The role of fibulin-2 in human heart pathologies is yet to be investigated. An animal, microarray study showed that fibulin-5 is downregulated in heart of young rats with induced ischemia, but not in the old ones [64]. In this study, the different type of response in relation to age is emphasized; in fact, in young rats, the postischemia events are still characterized by
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Table 3 Summary of the fibulins expression in the human cardiovascular system Fibulin Development Pathology
Heart
Atrial fibrillation # Fibulin-1 Endocardial cushion; ventricular morphogenesis Fibulin-2 Endocardial cushion Fibulin-4 Semilunar valve cushion Fibulin-5 Semilunar valve cushion
Arteries Fibulin-1 Coronary vessels
Cutis laxa syndrome related supravalvular aortic stenosis (mutation) Atherosclerosis "; diabetic matrix changes "; arterial stiffness "; aortic dissection #
Fibulin-2 Vasculature elastic fiber formation
Aortic dissection #
Fibulin-4 Vasculature elastic fiber formation
Cutis laxa syndrome related aortic dissection (mutation); lethal arteriopathy syndrome (mutation); aortic dissection #
Fibulin-5 Vasculature elastic fiber formation
Thoracic aortic dissection #; calcified thoracic aneurysm #
Plasma Fibulin-1
Fibulin-4
Type 2 diabetes "; aortic valve stenosis "; atrial fibrillation "; arterial stiffness "; GPS (mutation, lack of variant D) Thoracic aortic aneurysm #
remodeling-like features while in the elderly this capacity is lost, and they have an upregulation of injury-related genes. In human, fibulin-5 missense mutation leads to cutis laxa syndrome characterized by supravalvular aortic stenosis (AS) and peripheral pulmonary artery stenosis beside other connective disorder at several organs including skin, lungs, and intestine (Table 3) [65].
7. CIRCULATING FIBULINS Besides being ECM proteins, fibulin-1, -2, and -4 have been shown to be present in blood. Human fibulin-1 is present at a high concentration in
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plasma, ca. 30–50 μg/ml [66], while the concentration of fibulin-2 is much lower level around 20 ng/ml [2], and fibulin-4 is present only as a fragment at a concentration of 1.2 nmol/l [67]. Plasma fibulin-1 has displayed a potential as biomarker for cardiovascular diseases, first indicated from a study showing that the concentration of fibulin-1 is increased in T2DM, when measured both in extracts of arterial tissue and also in plasma [45]. Second, the concentration of plasma fibulin-1 was shown to be associated with measures of arterial stiffness, blood pressure, and glycemic status in a cohort of 305 well-characterized patients with T2DM [45]. Moreover, data from a 15-year follow-up study showed that high-plasma fibulin-1 concentrations among patients with T2DM were independently predictive of mortality with a hazard ratio similar to that of plasma cholesterol [45]. The associations of plasma fibulin-1 with glycemia, arterial compliance, and hypertension have subsequently been observed in other studies [68–70]. Besides, data from cross-sectional and randomized clinical trials show that individuals treated with metformin have reduced fibulin-1 levels [70]. This is interesting, since metformin is the only antidiabetic drug with proven beneficial effects on cardiovascular end points. Taken together, these results suggested that fibulin-1 is involved in arterial disease in T2DM and that the circulating concentration may serve as a biomarker for vascular ECM changes as part of a diabetic arteriopathy. Recently, knowledge about plasma fibulin-1 as biomarker has been expanded since it has been shown that fibulin-1 levels correlate not only to arterial stiffness, as in diabetes, but also to different cardiac conditions, which are characterized by fibrosis. Plasma levels of fibulin-1 correlate with N-terminal pro-brain natriuretic peptide, an indicator of myocardial stress in patients with heart failure, arrhythmias, ischemia, and increased filling pressure, levels in Africans [71]. Furthermore, fibulin-1 was reported to be significantly higher in patients with AS and patients with AFLI in combination with coronary artery disease, compared to patients with coronary artery disease alone [72], indicating that fibulin-1 could reflect cardiac fibrosis. Another recent study found fibulin-1 to be associated with the restrictive filling pattern and restrictive filling pressure in patients with AS, and also as a predictor of AFLI and cardiovascular mortality [73]. Thus, it seems that plasma fibulin-1 may reflect more than arterial changes and also be related to cardiovascular diseases involving alterations in ECM turnover. Interestingly, also the presence of several kidney diseases has been shown to correlate to increased levels of plasma fibulin-1 [74]. Plasma fibulin-1 correlates to
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serum creatinine as well as to age. The association between kidney disease and levels of plasma fibulin-1 is probably not related to glomerular filtration, since fibulin-1 has a size not likely to be filtrated. On the contrary, levels of plasma fibulin-1 may be related to increased vascular stiffness often seen in kidney patients. Moreover, treatment with low-dose spironolactone reduced plasma fibulin-1 levels in patients with T2DM and resistant hypertension randomized, placebo-controlled study [75]. This is in agreement with a possible regression of vascular remodeling due to the antihypertensive treatment. Plasma fibulin-1 has been found to be significantly decreased in unstable angina pectoris and acute MI patients compared to healthy controls in study conducted by Kawata et al. [76]. These results may appear in contrast to the above-reviewed results; however, differences in sample size and immunoassays could explain the differences. Plasma fibulin-4 has been measured in TAA patients and control subjects in a single study by Marshall et al. [67]. The percentage of detectable fibulin-4 fragments was lower in plasma from patients with aneurysm than control, suggesting that the increased turnover of fibulin-4 probably occurs during normal tissue homeostasis. To our knowledge, fibulin-2 has not been measured in plasma in relation to any cardiovascular pathology.
8. FIBULINS AND HEMOSTASIS Fibulin-1 binds to fibrinogen and its presence in blood may play a role in the coagulation and thrombi formation [11,66]. In fact, fibulin-1 mediates platelet adhesion via plasma protein bridge formation. Its presence in blood may account for its thrombotic aspects of atherosclerosis. The autosomal dominant giant platelet syndromes (GPSs) are a group of disorders characterized by macrothrombocytopenia (presence of abnormal giant platelets, with a diameter equal or superior to the diameter of a red cell, and a reduced total number of platelets with implication for blood clotting), renal manifestations and defects of the ear and the eye [77]. Lack of fibulin-1 variant D has been shown to be a determinant of some of the features of the phenotype of GPS [78]. GPS has initially been described as being caused by mutation of the gene MYH9 (myosin, heavy chain 9, nonmuscle, human gene), coding for the nonmuscle myosin heavy chain IIA, but this alone could not explain the phenotype. Studies by Toren and coworkers [78]
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on eight unrelated families affected by GPS found fibulin-1D to be lacking in all affected individuals while not all showed MYH9 expression.
9. FIBULINS AND POSSIBLE MECHANISM OF REGULATION The TGF-β plays an essential role during early cardiac and vascular development by inducing the formation of the cell layer surrounding the mesenchyme [79]. In adult vasculature, TGF-β modulates the SMCs response to injury by inducing their phenotypic transformation from contractile, quiescent status to a proliferative one expressing ECM molecules. TGF-β signals by binding its receptors through Smad 2 and 3 and activates pathways that mediate target gene expression. TGF-β can also act through a Smad-independent pathway. Many consecutive EGF-like repeats with cb motifs, which are characteristic of the fibulins are the hallmark of fibrillin [80,81] and TGF-β-binding protein [82]. There is a close relation between fibulin-1, -2, -4, and -5 and TGF-β regulation. Fibulin-4 deficiency upregulates TGF-β signaling through enhanced phosphorylation of Smad 2 [32]. Fibulin-4-deficient mice show an increased expression of angiotensin II type 1 receptor (AT1b) and consequently increased angiotensin II levels. This provokes upregulation of the TGF-β signaling that leads to aortic degeneration. In these mice, prenatal AT1 blockade via losartan, an AT1 antagonist prevents elastin fragmentation; postnatal treatment improves vascular contractility and survival without altering the architecture of the vessel wall [83]. Fibulin-5 is a gene target for TGF-β in fibroblasts and endothelial cells and regulates proliferation in a context-specific manner [84]. In vitro, addition of TGF-β to lungs fibroblast induces increase in fibulin-5 gene expression [85].
10. CONCLUSIONS AND PERSPECTIVES The fibulins are a diverse group of proteins with some common structural similarities. Of these, fibulin-1, -2, -4, and -5 have been shown to be relevant for cardiovascular biology and diseases. These fibulins play different roles in relation to matrix biology, i.e., in the buildup of elastic membranes and basement membranes, but their exact molecular roles are still elusive. Experimental studies and observations in humans moreover show that they may play roles in several cardiovascular diseases, particularly related to changes in the mechanical appearance of both large vessels and the heart.
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These diseases involve, for example, arterial aneurysms, stiffening of arteries, as for example in diabetes, and valvular heart disease. Moreover, fibulins may play a role in relation to thrombosis; however, a putative role in atherogenesis is not clear. Fibulin-1 circulates in high amounts in plasma and has been shown to be associated with several cardiovascular conditions with increased stiffness or fibrosis in the arteries or the heart.
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Fibulins and Their Role in Cardiovascular Biology and Disease Claudia Cangemi*, Maria Lyck Hansen*, William Scott Argraves†,w, Lars Melholt Rasmussen*,1 *Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark † Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina, USA 1 Corresponding author: e-mail address: [email protected]
Contents 1. Introduction 2. Genes, Expression and Biochemistry 3. Genetically Modified Animals 4. Expression of Fibulins in Heart and Vasculature During Development 5. Fibulins in Arterial Disease 6. Fibulins and Heart Disease 7. Circulating Fibulins 8. Fibulins and Hemostasis 9. Fibulins and Possible Mechanism of Regulation 10. Conclusions and Perspectives References
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Abstract Fibulins are a group of extracellular matrix proteins of which many are present in high amounts in the cardiovascular system. They share common biochemical properties and are often found in relation to basement membranes or elastic fibers. Observations in humans with specific mutations in fibulin genes, together with results from genetically engineered mice and data from human cardiovascular tissue suggest that the fibulin family of proteins play important functional roles in the cardiovascular system. Moreover, fibulin-1 circulates in high concentrations in plasma and may function as a cardiovascular disease marker.
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Deceased.
Advances in Clinical Chemistry, Volume 67 ISSN 0065-2423 http://dx.doi.org/10.1016/bs.acc.2014.09.008
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ABBREVIATIONS ADAMTS-1 a disintegrin and metalloproteinase with thrombospondin motifs-1 AFLI atrial fibrillation AS aortic stenosis AT1 angiotensin II type 1 cb calcium binding E embryonic day ECM extracellular matrix EGF epidermal growth factor fbln fibulin, mouse gene FBLN fibulin, human gene GPS giant platelet syndromes MI myocardial infarction MR mitral regurgitation MYH9 myosin, heavy chain 9, nonmuscle, human gene SMC smooth muscle cells T2DM type 2 diabetes mellitus TAA thoracic aortic aneurysm TAD thoracic aortic dissection TGF-β transforming growth factor-beta WT wild type
1. INTRODUCTION Fibulins are a family of eight extracellular matrix (ECM) glycoproteins, fibulin-1 to -8, characterized by a modular structure: they have epidermal growth factor (EGF)-like modules followed by calcium-binding (cb)-EGF-like modules, and they all contain a unique fibulin C-terminal domain (Table 1). Fibulin-1 and -2 constitute the subgroup of the “long fibulins”; they are larger and have an extra domain with anaphylatoxin units. These long fibulins were the first to be discovered in the beginning of the 1990s [1,2] and are capable of forming dimers [3–5]. Fibulin-3, -4, -5, and -7 belong to the second subgroup of the “short fibulins.” The short fibulins show similarities in structure and exist as monomers [6]. Fibulin-6 and -8 are also known as the “hemicentins” (hemicentin-1 and -2, respectively) and have aminoterminal von Willebrand domains followed by a long module of tandem immunoglobulin repeats [7,8]. The fibulins, although sharing similarities in terms of biochemical structures and location, have quite different functions and binding partners.
Table 1 Structure, chromosome localization, and expression of the fibulins in the cardiovascular system Name
Long fibulins
Short fibulins
Hemicentin
Structure
Size
Chromosome
Heart
Artery
Plasma
Fibulin-1 BM-90
90–100 kDa
22q13.31
✓
✓
✓
Fibulin-2
195 kDa
3p24–p25
✓
✓
✓
Fibulin-3 S1-5, T16, or EFEMP1
50 kDa
2p16
Fibulin-4 MBP1 or EFEMP2 UPH1, H411
50 kDa
11q13
✓
✓
✓
Fibulin-5 EVEC or DANCE UP50
65 kDa
14q32.1
✓
✓
Fibulin-7 TM14
48 kDa
2q13
Fibulin-6 Hemicentin-1
600 kDa
1q25.3
Fibulin-8 Hemicentin-2
600 kDa
9q34.11
FIB, fibulin module; EGF, epidermal growth factor-like domain; Cb-EGF, calcium-binding EGF; Mod. Cb-EGF, modified Cb-EGF; Inc. Cb-EGF, incomplete Cb-EGF; As, anaphylatoxin-like domain; Su, Sushi domain; vW, von Willebrand motif; Igs, immunoglobulin-like domain; TSPs, thrombospondin-1 motif; NID, nidogen-like domain.
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Fibulin-1, -2, -4, and -5 have been described in relation to the cardiovascular system in both healthy and pathological conditions and will therefore be the main focus of this chapter.
2. GENES, EXPRESSION AND BIOCHEMISTRY Fibulin-1 (FBLN-1; and also known as BM-90) was discovered by Argraves and coworkers in 1989 [1]. The gene for fibulin-1 was mapped on the long arm of human chromosome 22 (22q13.3) [9]. Fibulin-1 is a cb 90 kDa protein expressed in the ECM in many organs, often in relation to basement membranes, but it is also a plasma protein in blood having been shown to interact with fibrinogen [10,11]. Fibulin-1 has been shown to interact with integrins and versican [12], pointing toward a role in cell adhesion and mobility, while the ability of interacting with ADAMTS-1 (a disintegrin and metalloproteinase with thrombospondin motifs-1) [13] and nidogen [14] may suggest a role in matrix remodeling. Fibulin-1 has four alternative splicing variants: fibulin-1A, -1B, -1C, and -1D. They differ in their terminal fibulin domain in both length and amino acid sequence. At least fibulin-1C and -1D have been shown to have a different kind of interaction partner in the ECM [4,15], implying possible diverse functions of the different isoforms [16,17]. Fibulin-2 was discovered from sequence analysis of cDNA clones obtained from a mouse fibroblast library by Pan et al. in 1993 [2]. This fibulin showed 43% identity compared to fibulin-1 differing mainly in the first domain characterized by three anaphylatoxin-related segments. The fibulin-2 gene was localized by in situ hybridization to the p24–p25 region of human chromosome 3 and to the band D–E of mouse chromosome 6 [18]. Under physiological conditions, fibulin-2 is found in dimers consisting of two 195 kDa units covalently bonded [5]. Fibulin-2 is more often colocalized with fibulin-1, and it is also involved in matrix remodeling and cell motility. These two fibulins display a similar, but not entirely overlapping, repertoire of ECM protein-binding partners, and some animal studies indicate that fibulin-1 may compensate for the lack of fibulin-2 regarding some functions (further described in Section 3). Furthermore, fibulin-2 has also been shown to have a role in elastogenesis and to interact with type IV collagen [19].
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Table 2 General functions of fibulin-1, -2, -4, and -5 Function Fibulins involved
Cell adhesion and mobility
Fibulin-1 Fibulin-5
Matrix remodeling
Fibulin-1 Fibulin-2
Elastogenesis
Fibulin-2 Fibulin-4 Fibulin-5
The gene for fibulin-4, also known as EFEMP2 (EGF-containing fibulin-like ECM protein 2), has been located in chromosome 11 at 11q13.1 [20]. Fibulin-4 mRNA has been shown to be widely expressed in various tissues throughout the body and in particular at high levels in the vasculature [21]. This 50 kDa protein has a crucial role in elastogenesis through its binding capacity to tropoelastin and lysyl oxidase [22]. Fibulin-5, also known as EVEC or DANCE, is a 54 kDa integrinbinding ECM protein that mediates endothelial cell adhesion and, through its calcium-dependent elastin binding, has an essential function in the organization of elastic fibers [23]. The gene coding fibulin-5 is located at 14q31 [24]. The main functions of fibulin-1, -2, -4, and -5 are summarized in Table 2.
3. GENETICALLY MODIFIED ANIMALS Several animal knockout studies have been carried out since the discovery of fibulins to unravel their biological role of these proteins in vivo. The fibulin-1-deficient mice die perinatally suffering from impaired endothelial function of small blood vessels and severe defects in the basement membranes of many organs, including the kidneys and lungs resulting in fatal hemorrhaging and organ malformations [25]. Thus, no adult animals have been available for further studies. Fibulin-1 is essential during embryonic development since it is required for directing the migration and survival of cranial neural crest cell [26]. The development of
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pharyngeal glands, craniofacial skeleton, cranial nerves, aortic arch arteries, cardiac outflow tract, and cephalic blood vessels is dependent on a proper migration of the neural crest during embryo development. Thus, fibulin-1 is essential for the proper development of the vascular system, the kidneys, and the lungs. In the embryonic heart, fibulin-1 regulates versican-dependent events in ventricular morphogenesis by promoting ADAMTS-1 cleavage of versican leading to suppression of trabecular cardiomyocyte proliferation [27]. Fibulin-2 null mice develop normally and are phenotypically identical to their wild-type (WT) littermates. The function of fibulin-2 in embryonic development is probably dispensed in the mouse by functional redundancy with fibulin-1 [28]. In adult mice, fibulin-2 has been shown to play an important role in cardiac remodeling after experimentally induced myocardial infarction (MI). The knockout animals had less ventricular dysfunctions and hypertrophy and a better overall survival than the WT [29]. The reduced ventricular remodeling of the fibulin-2 null mouse is due to inhibition of the angiotensin II-induced TGF-β (transforming growth factorbeta) cardiac remodeling [30]. Disruption of fibulin-4 in mouse caused perinatal lethality due to elastic structures abnormalities at several organs, despite the normal amounts of tropoelastin [31]. The embryonic phenotype of the fbln4/ homozygous was characterized by narrow descending aorta and aorta tortuosity. Hanada et al. [32] generated later a mouse with reduced expression of fibulin-4 (fbln4R/R). This had quite a severe cardiovascular phenotype including vascular tortuosity, dilated ascending aorta, and increased heart size. Furthermore, a number of phenotypes, including loose skin and emphysema, typical of abnormal elastic fibers assembly, were described. The phenotype of fbln4R/R mouse resembles that typical phenotype of human connective tissue disorders such as Marfan syndrome. fbln4R/R mice develop severe aneurysm formation and aortic stiffening, followed by aortic dissection later in life. Fibulin-5 is responsible for the elastic fibers organization (polymerization of elastin). Fibulin-5-null mice exhibit lung and vasculature malformations [23,33]. The aorta of fibulin-5 null mouse is tortuous, elongated, and has disrupted elastic laminae, this defect being more severe in the outer lamina compared to the internal lamina [33]. However, these deficiencies are distinct from those resulting from fibulin-1 and -4 inactivation, suggesting that fibulin-1, -4 and -5 share structural but not functional redundancy during development. As well as fbln4R/R, fibulin-5 (fbln-5)-deficient mice were characterized by tortuous aorta with loss of compliance and a profound
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elastinopathy of the skin. Moreover, the fibulin-5 null mice show a significant increase of systolic blood pressure and pulse pressure compared to the WT. However, fibulin-5-deficient mice do not develop aneurysms, indicating that probably fibulin-4 is directly involved in the development of the pathology through TGF-β signaling.
4. EXPRESSION OF FIBULINS IN HEART AND VASCULATURE DURING DEVELOPMENT During cardiogenesis, fibulin-1 and -2 are present at high levels at sites of epithelial–mesenchymal transformation, endocardial cushion, and coronary vessels [34,35]. Fibulin-1 is also present in high amounts in the embryonic myocardium [36]. Fibulin-1, in particular, regulates versican-dependent events during ventricular morphogenesis [27]. Both fibulins are also present in the vessels with highest concentration in the adventitial area [37]. During embryonic development, fibulin-1 and -2 are also present at other locations such as the neural crest and the developing cartilage, tooth, and hair follicles [38], fibulin-2 expression being less prominent than fibulin-1 [38]. The high expression of fibulin-1 and -2 in the embryo is transient in most of the tissues and disappears during development. In the adult stage, fibulin-1 and -2 are present in the arterial walls and in the cardiac valves [34]. Fibulin-4 starts to be expressed in mouse embryo before the embryonic day (E) 14.5, and it is primarily involved in elastic fibers formation and then crucial for the development of the cardiovascular system [31]. The data regarding fibulin-4 expression during development are poor and mainly extrapolated from the knockout studies. Fibulin-5 is expressed in mouse embryos from E10.5 and its level becomes higher in the developing medial layer and endothelial cells of the latter-stage embryo E16.5 [39]. Moreover, fibulin-2 and -5 are both essential for the elastic laminae formation during postnatal development. Fibulin-2 is located in the subendothelial matrix of the blood vessels, while fibulin-5 is present throughout the whole vessel wall [40]. In the adult mice, fibulin-5 expression is attenuated and remains detectable only in the myometrial arteries, which are characterized by continuous angiogenesis. Although, fibulin-5 can be reactivated in adult blood vessels in response to injury [41]. Thus, fibulin-5 has its main role in embryonic vasculature formation, especially of the large vessels, in those processes involving fast smooth muscle and endothelial cell growth; later in life its activity is mainly related to vascular remodeling.
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In human, fibulin-4 and -5 are detectable in developing semilunar valve cushions as early as week 4 of gestation. Gene expression analyses showed significantly decreasing fibulin-4 levels in adolescent and in adult leaflets when compared with first- and second-trimester tissues; whereas fibulin-5 expression remained constant throughout the lifetime [42]. No information about fibulin-4 and -5 expression during human development in other organs is available to our knowledge.
5. FIBULINS IN ARTERIAL DISEASE The ECM has central importance for the blood vessels, in both physiological and pathological conditions, because not only it determines their mechanic characteristics but also it is involved in essential cellular activities such as migration and proliferation of smooth muscle cells (SMCs) and endothelial cells. The fibulins, as components of the ECM, have been shown to play an active role in these processes. Fibulin-1 is present throughout the arterial wall but its expression is higher in the outermost layer of the tunica media in association with the external elastic lamina (Fig. 1). Fibulin-1 has been associated with vascular calcification processes in mouse. Vascular calcification is a common clinical
Figure 1 Fibulin-1 and elastin in arterial wall. Shown is a cross-section of internal mammary artery stained using antifibulin-1 antibodies (A) and elastin Verhoeff staining (B). The Verhoeff stains elastin black. Most antifibulin-1 staining is in the tunica adventitia (A) with some staining at the media layer (M) close to elastic fibers and in the tunica intima (I).
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complication of diabetes and renal diseases, as it is characterized by osteoblastic transformation of the vascular SMCs. A microarray study showed that fibulin-1 was fourfold upregulated in mineralizing mouse vascular SMC [43]. Also, fibulin-1 has been shown to be a component of coronary artery atherosclerotic lesions in human [11]. In the lesions, fibulin-1 immunostaining colocalizes with fibrinogen staining [11], but the pathological mechanisms beyond are yet to be determined. Moreover, fibulin-1 expression appears to be related to arterial stiffness in human arteries. In a genomic study by Durier and coworkers [44], fibulin-1 gene expression was higher in human aorta from patients with increase arterial stiffness than in those with distensible aorta. Furthermore, fibulin-1 has been recently identified as the most upregulated transcript in nonatherosclerotic arterial tissue from patients with type 2 diabetes mellitus (T2DM) [45]. The prevalence of thoracic aortic aneurysm (TAA) is lower in patients with T2DM, and they have a decreased risk of progression and rupture of abdominal aortic aneurysms [46]. These indications altogether may suggest that the balance in expression of fibulin-1 is essential for a correct functioning of the vasculature and that this protein has an active role in vessels homeostasis. Fibulin-1 upregulation is associated with arterial stiffness and probably fibrotic elements in the vessels, as it is seen in diabetic arteriopathy; while its downregulation is connected to aortic dissection and increase in inflammatory responses. In healthy vasculature, fibulin-2 is present around the internal elastic lamina [47] and binds to versican, creating a network that interact with hyaluronan [48]. In mouse, fibulin-2 is present in vascular lesions, both atherosclerotic lesions and those induced by a periadventitial collar, and its expression appears to orchestrate the SMC response to injury. In particular, fibulin-2 upregulation in these lesions leads to enhanced SMC migration during repair mechanisms [49]. In estradiol-treated monkeys, fibulin-2 has been found highly expressed in atherosclerotic regions of the iliac artery, possibly because of its role in the lesion repair mechanisms [50]. Fibulin-2 was absent in regions with macrophages, thus it does not appear to be involved in the inflammatory processes. In aortic tissue of patients with aortic Stanford type A dissection and acute aortic dissection, fibulin-1 and -2 expression were downregulated [51,52]. Aortic dissection can be due to both inherited connective tissue disorders and acquired conditions such as chronic hypertension. A common characteristic in the etiology of aortic dissection is that the ECM undergoes accelerated degradation, apoptosis, and elastolysis leading to SMC necrosis
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and fibrosis of the elastic fibers. The significance of the connection of fibulin-1 and -2 to these remains to be made clear. Reduced expression of fibulin-4 in mouse leads to formation of aneurysms and aortic dissection due to elastic lamina disruption and cardiac abnormalities. The abnormalities in the vessel wall are due to both an aberrant deposition of elastin characterized by granular appearance in outer lamina and a disarray of the elastic fibers and matrix accumulation in the inner layers [32] and abnormal SMCs phenotype because of a reduced expression of contractile protein [53]. Fibulin-4-deficient mice have tortuous and elongated aortas with dilatation of the ascending tract, and they also have significantly higher pulse pressure compared to the WT probably due the aortic insufficiency [32]. In humans, fibulin-4 mutations were found in cutis laxa type I (autosomal recessive) patients; these individuals are characterized by a modest skin phenotype (inelastic skin) and predominant cardiovascular phenotype characterized by aortic aneurysms and arterial tortuosity and stenosis [54]. In addition to what has been shown by the animal studies, fibulin-4 impairment is also associated with TGF-β upregulation through Smad2 phosphorylation in human [54]. A novel mutation of fibulin-4 has recently been described in a cohort of Indian infants with lethal arteriopathy syndrome [55] underlining the importance of fibulin-4 in human elastogenesis. Furthermore, fibulin-4 expression was found to be decreased in the aortic wall of patients operated for acute and chronic ascending aortic dissection [56]. Fibulin-5 has a role as an inhibitor of SMCs proliferation and migration, and deletion of this protein causes abnormal vascular remodeling. Ligated carotid artery of fibulin-5-deficient mice showed increased vessel diameter and increased neointimal formation compared to WT. The carotid artery of these mice was also less elastic. Cultured vascular SMCs, isolated from fibulin-5-deficient mice, have enhanced proliferative and migratory response to mitogenic stimuli [57]; this was suppressed by overexpression of fibulin-5. In human, fibulin-5 has been found upregulated in the later stage of induced neointimal lesions and in the endothelial layer of atherosclerotic plaques [39,58]. Thus, fibulin-5 has a protective role orchestrating SMC turnover in physiological conditions and regulating SMC proliferation in response to injuries. At the same time, fibulin-5 contributes to the mechanic stability of the vessels through its interaction with elastin. Fibulin-5 is downregulated in the aortic wall of patients with thoracic aortic dissection (TAD). TAD is also characterized by degeneration and fragmentation of elastin in the arterial wall, which is probably due to fibulin-5
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reduction [59]. In addition, fibulin-5 was found to be downregulated in patients with calcified thoracic aneurysm in a recent proteomic study [60].
6. FIBULINS AND HEART DISEASE The fibulins in the heart are of central importance in several mechanisms behind the pathological changes. There are many evidences that link fibulin-1 to valvular heart pathologies, atrial fibrillation (AFLI), and cardiac impairment in general. Mitral regurgitation (MR) is a valvular heart disease that occurs when the mitral valve does not close properly during the systolic phase. This condition causes left ventricular remodeling through enhanced turnover of essential noncollagen ECM components. In a dog model of MR, a global decrease of the expression of ECM genes has been reported. In this study, fibulin-1 was almost twofold downregulated in MR [61]. Interestingly, also TGF-β was downregulated at the same degree suggesting a possible downstream effect on the synthesis of the ECM components. A pathway analysis of the dysregulated genes in the dog MR model identified a network of involved genes similar to the ones being influenced in the Marfan syndrome, MI, and aneurysm formation. Furthermore, fibulin-1 expression in atrial tissue of patients with AFLI was found downregulated by proteomics approach [62] (the study had though some limitations due to the small population size). Moreover, in a microarray study, fibulin-1 mRNA appeared to be upregulated in myocardial specimens from patients with coronary artery disease and patients with dilated cardiomyopathy compared to those from a nondiseased heart [63]. Loss of fibulin-2 in mouse protects against cardiac rupture and ventricular dysfunction and improved survival after MI [29]. Absence of fibulin-2 decreased the inflammatory response and collagen I and III deposition after MI reducing therefore ventricular remodeling. This could be attributed to the reduced upregulation of TGF-β signaling and other ECM proteins after MI of the fibulin-2-deficient mice compared to WT. Also, the reduction of the TGF-β signaling has been shown to attenuate angiotensin II-induced cardiac hypertrophy in the fibulin-2-deficient animals compared to the WT [30]. The role of fibulin-2 in human heart pathologies is yet to be investigated. An animal, microarray study showed that fibulin-5 is downregulated in heart of young rats with induced ischemia, but not in the old ones [64]. In this study, the different type of response in relation to age is emphasized; in fact, in young rats, the postischemia events are still characterized by
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Table 3 Summary of the fibulins expression in the human cardiovascular system Fibulin Development Pathology
Heart
Atrial fibrillation # Fibulin-1 Endocardial cushion; ventricular morphogenesis Fibulin-2 Endocardial cushion Fibulin-4 Semilunar valve cushion Fibulin-5 Semilunar valve cushion
Arteries Fibulin-1 Coronary vessels
Cutis laxa syndrome related supravalvular aortic stenosis (mutation) Atherosclerosis "; diabetic matrix changes "; arterial stiffness "; aortic dissection #
Fibulin-2 Vasculature elastic fiber formation
Aortic dissection #
Fibulin-4 Vasculature elastic fiber formation
Cutis laxa syndrome related aortic dissection (mutation); lethal arteriopathy syndrome (mutation); aortic dissection #
Fibulin-5 Vasculature elastic fiber formation
Thoracic aortic dissection #; calcified thoracic aneurysm #
Plasma Fibulin-1
Fibulin-4
Type 2 diabetes "; aortic valve stenosis "; atrial fibrillation "; arterial stiffness "; GPS (mutation, lack of variant D) Thoracic aortic aneurysm #
remodeling-like features while in the elderly this capacity is lost, and they have an upregulation of injury-related genes. In human, fibulin-5 missense mutation leads to cutis laxa syndrome characterized by supravalvular aortic stenosis (AS) and peripheral pulmonary artery stenosis beside other connective disorder at several organs including skin, lungs, and intestine (Table 3) [65].
7. CIRCULATING FIBULINS Besides being ECM proteins, fibulin-1, -2, and -4 have been shown to be present in blood. Human fibulin-1 is present at a high concentration in
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plasma, ca. 30–50 μg/ml [66], while the concentration of fibulin-2 is much lower level around 20 ng/ml [2], and fibulin-4 is present only as a fragment at a concentration of 1.2 nmol/l [67]. Plasma fibulin-1 has displayed a potential as biomarker for cardiovascular diseases, first indicated from a study showing that the concentration of fibulin-1 is increased in T2DM, when measured both in extracts of arterial tissue and also in plasma [45]. Second, the concentration of plasma fibulin-1 was shown to be associated with measures of arterial stiffness, blood pressure, and glycemic status in a cohort of 305 well-characterized patients with T2DM [45]. Moreover, data from a 15-year follow-up study showed that high-plasma fibulin-1 concentrations among patients with T2DM were independently predictive of mortality with a hazard ratio similar to that of plasma cholesterol [45]. The associations of plasma fibulin-1 with glycemia, arterial compliance, and hypertension have subsequently been observed in other studies [68–70]. Besides, data from cross-sectional and randomized clinical trials show that individuals treated with metformin have reduced fibulin-1 levels [70]. This is interesting, since metformin is the only antidiabetic drug with proven beneficial effects on cardiovascular end points. Taken together, these results suggested that fibulin-1 is involved in arterial disease in T2DM and that the circulating concentration may serve as a biomarker for vascular ECM changes as part of a diabetic arteriopathy. Recently, knowledge about plasma fibulin-1 as biomarker has been expanded since it has been shown that fibulin-1 levels correlate not only to arterial stiffness, as in diabetes, but also to different cardiac conditions, which are characterized by fibrosis. Plasma levels of fibulin-1 correlate with N-terminal pro-brain natriuretic peptide, an indicator of myocardial stress in patients with heart failure, arrhythmias, ischemia, and increased filling pressure, levels in Africans [71]. Furthermore, fibulin-1 was reported to be significantly higher in patients with AS and patients with AFLI in combination with coronary artery disease, compared to patients with coronary artery disease alone [72], indicating that fibulin-1 could reflect cardiac fibrosis. Another recent study found fibulin-1 to be associated with the restrictive filling pattern and restrictive filling pressure in patients with AS, and also as a predictor of AFLI and cardiovascular mortality [73]. Thus, it seems that plasma fibulin-1 may reflect more than arterial changes and also be related to cardiovascular diseases involving alterations in ECM turnover. Interestingly, also the presence of several kidney diseases has been shown to correlate to increased levels of plasma fibulin-1 [74]. Plasma fibulin-1 correlates to
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serum creatinine as well as to age. The association between kidney disease and levels of plasma fibulin-1 is probably not related to glomerular filtration, since fibulin-1 has a size not likely to be filtrated. On the contrary, levels of plasma fibulin-1 may be related to increased vascular stiffness often seen in kidney patients. Moreover, treatment with low-dose spironolactone reduced plasma fibulin-1 levels in patients with T2DM and resistant hypertension randomized, placebo-controlled study [75]. This is in agreement with a possible regression of vascular remodeling due to the antihypertensive treatment. Plasma fibulin-1 has been found to be significantly decreased in unstable angina pectoris and acute MI patients compared to healthy controls in study conducted by Kawata et al. [76]. These results may appear in contrast to the above-reviewed results; however, differences in sample size and immunoassays could explain the differences. Plasma fibulin-4 has been measured in TAA patients and control subjects in a single study by Marshall et al. [67]. The percentage of detectable fibulin-4 fragments was lower in plasma from patients with aneurysm than control, suggesting that the increased turnover of fibulin-4 probably occurs during normal tissue homeostasis. To our knowledge, fibulin-2 has not been measured in plasma in relation to any cardiovascular pathology.
8. FIBULINS AND HEMOSTASIS Fibulin-1 binds to fibrinogen and its presence in blood may play a role in the coagulation and thrombi formation [11,66]. In fact, fibulin-1 mediates platelet adhesion via plasma protein bridge formation. Its presence in blood may account for its thrombotic aspects of atherosclerosis. The autosomal dominant giant platelet syndromes (GPSs) are a group of disorders characterized by macrothrombocytopenia (presence of abnormal giant platelets, with a diameter equal or superior to the diameter of a red cell, and a reduced total number of platelets with implication for blood clotting), renal manifestations and defects of the ear and the eye [77]. Lack of fibulin-1 variant D has been shown to be a determinant of some of the features of the phenotype of GPS [78]. GPS has initially been described as being caused by mutation of the gene MYH9 (myosin, heavy chain 9, nonmuscle, human gene), coding for the nonmuscle myosin heavy chain IIA, but this alone could not explain the phenotype. Studies by Toren and coworkers [78]
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on eight unrelated families affected by GPS found fibulin-1D to be lacking in all affected individuals while not all showed MYH9 expression.
9. FIBULINS AND POSSIBLE MECHANISM OF REGULATION The TGF-β plays an essential role during early cardiac and vascular development by inducing the formation of the cell layer surrounding the mesenchyme [79]. In adult vasculature, TGF-β modulates the SMCs response to injury by inducing their phenotypic transformation from contractile, quiescent status to a proliferative one expressing ECM molecules. TGF-β signals by binding its receptors through Smad 2 and 3 and activates pathways that mediate target gene expression. TGF-β can also act through a Smad-independent pathway. Many consecutive EGF-like repeats with cb motifs, which are characteristic of the fibulins are the hallmark of fibrillin [80,81] and TGF-β-binding protein [82]. There is a close relation between fibulin-1, -2, -4, and -5 and TGF-β regulation. Fibulin-4 deficiency upregulates TGF-β signaling through enhanced phosphorylation of Smad 2 [32]. Fibulin-4-deficient mice show an increased expression of angiotensin II type 1 receptor (AT1b) and consequently increased angiotensin II levels. This provokes upregulation of the TGF-β signaling that leads to aortic degeneration. In these mice, prenatal AT1 blockade via losartan, an AT1 antagonist prevents elastin fragmentation; postnatal treatment improves vascular contractility and survival without altering the architecture of the vessel wall [83]. Fibulin-5 is a gene target for TGF-β in fibroblasts and endothelial cells and regulates proliferation in a context-specific manner [84]. In vitro, addition of TGF-β to lungs fibroblast induces increase in fibulin-5 gene expression [85].
10. CONCLUSIONS AND PERSPECTIVES The fibulins are a diverse group of proteins with some common structural similarities. Of these, fibulin-1, -2, -4, and -5 have been shown to be relevant for cardiovascular biology and diseases. These fibulins play different roles in relation to matrix biology, i.e., in the buildup of elastic membranes and basement membranes, but their exact molecular roles are still elusive. Experimental studies and observations in humans moreover show that they may play roles in several cardiovascular diseases, particularly related to changes in the mechanical appearance of both large vessels and the heart.
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These diseases involve, for example, arterial aneurysms, stiffening of arteries, as for example in diabetes, and valvular heart disease. Moreover, fibulins may play a role in relation to thrombosis; however, a putative role in atherogenesis is not clear. Fibulin-1 circulates in high amounts in plasma and has been shown to be associated with several cardiovascular conditions with increased stiffness or fibrosis in the arteries or the heart.
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