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Cardiovascular Research 2005 65(4):793-802; doi:10.1016/j.cardiores.2004.11.010
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Copyright © 2004, European Society of Cardiology

Annexins and Ca2+ handling in the heart

Emmanuel Camors, Virginie Monceau and Daniéle Charlemagne*

INSERM U572, IFR Circulation, Hôpital Lariboisière, 41 Bd de la Chapelle, 75475 Paris cedex 10, France

* Corresponding author. Tel.: +33 1 446 31725; fax: +33 1 487 42315. Email address: daniele.charlemagne{at}larib.inserm.fr

Received 4 August 2004; revised 8 November 2004; accepted 10 November 2004


   Abstract
Top
 Abstract
1. Introduction
 2. Overview of annexin...
 3. Myocardial annexins
 4. Conclusion
 Acknowledgment
 References
 
Annexins are a family of 13 proteins known to bind phospholipids (PL) in a Ca2+-dependent way. They are ubiquitous proteins and share a similar structure characterized by a conserved C-terminal domain with Ca2+ binding sites and a variable N-terminal domain. Depending on Ca2+ concentration, they have been reported to participate in a variety of membrane-related events such as exocytosis, endocytosis, apoptosis and binding to cytoskeletal proteins. They have also been reported to regulate protein activities. This review will focus on annexins in the heart, and particularly on annexins A2, A5, A6 and A7. Annexin A2 has been found in endothelial cells and reported to play a central role in control of plasmin-mediated processes. Annexin A5 is mainly localized in cardiomyocytes. However, it could be relocated to interstitial tissue in ischemic and failing hearts or it could be externalized and exhibit a proapoptotic effect in cardiomyocytes. Annexin A6 is the most abundant annexin in the heart, and has been localized in various cell types including myocytes. Overexpression of annexin A6 has underlined physiological alterations in contractile mechanics leading to dilated cardiomyopathy, whereas knockout has been found to induce faster changes in Ca2+ transient and increased contractility, suggesting a negative inotropic role for annexin A6. Annexin A7 is expressed in heart and skeletal muscle. In annexin A7 null mutant mice decreases in the force–frequency relationship were observed in adult cardiomyocytes, consistent with regulation of Ca2+ handling. In conclusion, while annexin A2 was involved in regulation of fibrin homeostasis, alterations in expression and activity of annexins A5, A6 and A7 have been associated with regulation of Ca2+ handling in the heart, but the target of each annexin has not yet been identified.

KEYWORDS Annexin; Ca2+ handling; Heart


   1. Introduction
Top
 Abstract
 1. Introduction
2. Overview of annexin...
 3. Myocardial annexins
 4. Conclusion
 Acknowledgment
 References
 
Cytoplasmic free Ca2+ has crucial second-messenger functions in the regulation of numerous fundamental physiological processes such as excitation-contraction coupling, secretion, cell growth and cell-to-cell communication. In the myocardium, Ca2+-handling proteins contribute to the rise and fall of the intracellular free Ca2+ that induces contraction and relaxation. Ca2+ influx through sarcolemmal (SL) voltage-dependent L-type Ca2+ channels is responsible for the sarcoplasmic reticulum (SR) Ca2+ release by ryanodine receptors (RyR2) that leads to contraction. Ca2+ efflux by the Na+/Ca2+exchanger (NCX) and Ca2+ uptake by the SR Ca2+ ATPase (SERCA2) are responsible for the time course of the Ca2+ transient and relaxation.

Recently, in addition to the identification of physiological regulators including Ca2+, Mg2+ and β-adrenergic stimulation, modulation of Ca2+-handling proteins by regulatory factors has also been established [1,2]. Among these factors, Ca2+ binding proteins such as sorcin and AHNAK have been reported to regulate L-type Ca2+ channels [3,4] while calsequestrin, histidine-rich Ca2+ binding protein and sorcin have been found to regulate the SR Ca2+-release channel [5–7]. Finally, the regulatory factors of the NCX have never been clearly identified, although it has been suggested that annexins A2 and A6 modulate its activity [8,9].

What are annexins and why is it suggested that they play a role in Ca2+ handling? Annexins are a family of 13 Ca2+ binding proteins known to bind negatively charged phospholipids (PL) in a Ca2+-dependent way (for reviews, see Refs. [10–12]). They have been involved in Ca2+ signaling pathways [13] and exhibit all the properties required to belong to the family of Ca2+-handling regulatory proteins in the heart. However, the goal of this review is not to detail annexin properties and functions but rather to provide insight into their general biochemical properties related to Ca2+, then to present some recent findings on annexins present in myocardium and, where possible, discuss how they could account for some of the abnormalities observed in Ca2+ handling in heart failure.


   2. Overview of annexin properties and functions
Top
 Abstract
 1. Introduction
 2. Overview of annexin...
3. Myocardial annexins
 4. Conclusion
 Acknowledgment
 References
 
Annexins are ubiquitous proteins which present a high structural homology. They are characterized by a bipartite structure with a variable N-terminal domain and a conserved C-terminal domain (the core domain) representing the major part of annexins (Fig. 1). This latter domain is formed by four repeats of approximately 70 amino acids, except for annexin A6 which contains eight repeats. Each repeat contains an important {alpha}-helical domain carrying a Ca2+ binding site which has varying affinity depending on annexin core and PL (for review, see Ref. [10]). It is currently accepted that Ca2+ binding leads to conformational changes of the structure, with the hydrophobic part of the protein being exposed, leading in turn to oligomerization of annexins, high affinity for PL [10,11,14] and relocation to nuclear and plasma membranes [15,16]. However, the exact nature of these conformational changes is not yet clear and likely depends not only on Ca2+ but on pH and the annexin itself [17]. Some annexins (A5, A6, A7) have also been shown in lipid bilayers to form Ca2+ channel and to mediate Ca2+ influx [18,19]. However, the physiological possibility that annexins form active Ca2+ channels in vivo is still a matter of debate. The results from Kirsch et al. [20] supported this assumption. They recently demonstrated Ca2+ channel activity of annexins A2, A5 and A6 in matrix vesicles that represented the nucleation site for the mineralization process in cartilage. Moreover, Ca2+ influx in the presence of annexin A5 but not of other annexins was increased by interaction with collagen. Another report by Wang et al. [21] also emphasized the function of annexin A5 as a Ca2+ channel in chondrocyte mineralization. However, the question still remains as to whether only translocation to the membrane or transmembrane insertion is required for Ca2+ channel formation. The results of Langen et al. [17] on annexin A12 oligomers support transmembrane insertion of annexins under increased [Ca2+]i and decreased pH.


Figure 1
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  		Fig. 1 Structural organization of annexins.

 
Another property that is most likely common to all annexins is the ability to regulate physiological processes through the formation of complexes. For example, annexin A5 has been reported to be linked to extracellular matrix proteins such as collagen [19,20,22] and to cytoskeleton proteins such as actin [23,24]. Annexins A1, A2 and A6 are also actin binding proteins [24,25]. Thus annexins have been involved in various intra- and extracellular processes including mitogenic signal transduction, differentiation, membrane trafficking events, endocytosis and exocytosis (for review, see Ref. [12]). More recently, Babiychuck et al. and Draeger et al. have proposed the concept of annexins (particularly annexins A2, A6) as scaffolding proteins participating in lipid raft organization in smooth muscle [26] and skeletal muscle [27]. Their data showed that at high [Ca2+]i annexins A2 and A6 are codistributed with the raft-marker caveolin and participate in the organized raft domain, whereas annexins A1 and A4 are associated with the nonraft domain. These data on Ca2+-dependent PL binding capacities represent an overall feature of annexins but also suggest that each annexin has its own specificity. These assumptions were further supported by inhibition of phospholipase A2 activity. While Mira et al. [28] reported the importance of a specific Ca2+-binding site in the mechanism of inhibition by annexin A5, Kim et al. [29] found that various members of the annexin family suppressed cPLA2 activity with different mechanisms. Thus, PLA2 inhibition seems to depend not only on the core structure and Ca2+-dependent ability to bind PL but also on the N-terminal domain.

The N-terminal domain often balances the common feature of the core domain and confers functional specificity to each annexin by modulating its function. It could be short or longer, containing phosphorylation sites or specific binding domains (Fig. 1). Modulation of annexin properties could depend on formation of hydrophobic interactions between the short N-terminal domain, such as in annexins A3 and A5, and the corresponding core. For example, mutation of a Trp-5 by alanine in this domain of annexin A3 has been found to increase the affinity for PL binding and to enhance membrane permeabilization activity [30]. In annexins A7 and A11, the N-terminal domain is a GYP structure of 13 and 17 kDa, respectively, which has been involved in the binding of annexin A7 to sorcin [31]. In annexins A1 and A2, this domain has a particularly important role because it contains the phosphorylation sites and the binding domain of S100 protein A11 (annexin A1) or A10 (annexin A2). Binding of S100A10 to annexin A2 confers to this complex a membrane aggregation activity and the stimulation of tissue-plasminogen activator (t-PA)-dependent plasminogen activation [32,33].


   3. Myocardial annexins
Top
 Abstract
 1. Introduction
 2. Overview of annexin...
 3. Myocardial annexins
4. Conclusion
 Acknowledgment
 References
 
Annexins A1, A2, A4, A5, A6 and A7 have been detected in myocardium, where annexins A5 and A6 are the most abundant. They can be co-expressed in the same cell type but with their own localization. Endothelial cells expressed annexins A1, A2, A5 and A6 [34], smooth muscle cells expressed mainly annexins A2 and A6 [35], whereas cardiomyocytes expressed mainly annexins A4, A5, A6 and A7 [36–39]. The overall cellular [Ca2+]i and the very high submembranous local [Ca2+] in cardiomyocytes [40] should allow annexins to be present in or to rapidly translocate to SL and SR membranes. Recent findings underscoring the role of myocardial annexins as modulatory factors of Ca2+-handling proteins or even more as Ca2+-handling proteins will be summarized below.

3.1. Annexin A2
Annexin A2 is known as a cytoskeleton binding protein, localized underneath the plasma membrane and forming a heterotetramer with the S100 protein A10 [14]. In the myocardium, annexin A2 is localized in intramyocardial capillaries, extracellular matrix and in endothelial cells of the coronary arteries (Figs. 2 and 3Go). It is undetectable in ventricular and atrial myocytes [41]. The heterotetramer which reduces Ca2+ requirement for PL binding and activation of annexin A2 has been identified as a cell surface co-receptor for plasminogen and t-PA and therefore plays a central role in the control of plasmin-mediated processes and anti-thrombolytic properties [32,42]. In line with these results, Hajjar et al. [43] showed that t-PA binding occurred on the N-terminal domain of annexin A2 and was inhibited by homocysteine, providing a potential mechanism for the prothrombotic effect of homocysteine. From these studies, it can be speculated that alteration of annexin A2 expression at the surface of endothelial cells could lead to atherothrombotic vascular disease. Very recently, Lei et al. showed that annexin A2 is associated with Hsp90a and is up-regulated in endothelial cells of diabetic rat aorta, leading to increased plasmin activity. Furthermore, the authors suggested that changes in annexin A2 may be linked to clotting defects observed in diabetes [44]. Finally, generation of homozygous annexin A2-null mice clearly established that annexin A2 was involved both in regulation of fibrin homeostasis and in neoangiogenesis in vivo [45].


Figure 2
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  		Fig. 2 Localization of annexins A2, A5 and A6 in non-failing (A, B) and failing (dilated cardiomyopathy) (C,D) human hearts by immunohistochemistry. (A, C) Transverse tissue sections; (B, D) longitudinal tissue sections. Cryostat sections (7 µM) were fixed with acetone/methanol (1:1 for 20 min at –20 °C) and saturated with 5% BSA before incubation with anti-annexin A2, anti-annexin A5, anti-annexin A6. Annexin A2 was detected in intramyocardial capillaries, coronary arteries and in interstitial tissue (A). In failing heart, localization of annexin A2 remained similar whereas immunofluorescence was increased. Annexin A5 was detected in cytosol, SL, T-tubules (particularly evident in A) and intercalated discs (B) of cardiomyocytes in non-failing heart whereas it was practically absent from T-tubules (C) and translocated to interstitial space in failing hearts (C and D). Annexin A6 was detected in myocytes (cytosol, SL, T-tubules (A), intercalated discs (B)), interstitial tissue and coronary arteries of non-failing heart. In failing heart, labeling was similar but fluorescence was increased.

 

Figure 3
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  		Fig. 3 Localization of annexins A2, A5 and A6 in coronary artery from non-failing human hearts by immunohistochemistry.

 
In hypertrophied LV from hypertensive guinea pigs at the onset of heart failure and in failing human heart, the level of annexin A2 was found to be significantly increased (2.6-fold and 1.32-fold, respectively, compared with control LV) [38,41,46]. Immunolabeling of annexin A2 revealed intense staining of the interstitium between the cardiomyocytes and around the coronary arteries of failing hearts, correlated to this increase, whereas annexin A2 was still absent from cardiomyocytes (Fig. 2). Besides its role in endothelial cells, the interstitial localization of annexin A2 in heart failure and its known properties in membrane trafficking and collagen binding suggest that this annexin could be involved in the development of fibrosis and the organization of the extracellular matrix. In contrast, the absence of annexin A2 in cardiomyocytes from non-failing and failing hearts suggests that it does not play a major role in the regulation of Ca2+ handling in these cells.

3.2. Annexin A4
Annexin A4 has been mainly studied in fibroblasts and epithelial cells where it has an inhibitory effect on a Ca2+-dependent Cl-current by inhibiting CaM KII-ion channel interaction and preventing phosphorylation of the channel [47]. Only one report by Matteo et al. deals with annexin A4 in the heart. The authors showed that in human cardiomyocytes, annexin A4 is a cytosolic protein whose expression increases during heart failure. Moreover, the punctated longitudinal staining additionally observed in the non-failing atria was absent in the failing tissue, demonstrating loss of annexin A4 organization in the failing hearts [39].

3.3. Annexin A5
Annexin A5 is well known for its high affinity for PS. It is able to relocate to the membranes in response to rises in intracellular calcium [15,16], to form voltage-gated Ca2+ channels in lipid bilayers [48] and to mediate Ca2+ uptake by matrix vesicles of mineralizing bone [20,21]. However, with reference to this last property, Brachvogel et al. reported no difference in the development, growth and function of the skeleton in mice lacking annexin A5. It was suggested that these unexpected results could be explained by a compensatory effect of other members of the annexin family [49].

As an exogenous protein, annexin A5 has been shown to display a protective effect most likely by binding to PS and/or by forming two-dimensional arrays at the cell surface [50]. This binding of annexin A5 to PS has been accounted for its anticoagulant [51,52], antiapoptotic [50] and anti-inflammatory [53] effects. Although these properties have mainly been assigned to recombinant exogenous annexin A5 and may not necessarily be shared by cellular annexin A5, the presence of anti-annexin A5 antibodies in plasma from patients with antiphospholipid syndrome and thromboembolism strongly support a potent in vivo anticoagulant activity of annexin A5 [54].

Annexin A5 is one of the most abundant annexins in rat and human myocardium (3.7 µg/mg of total proteins) [38,55]. Although it was first reported to be absent from cardiomyocytes [56], it has since been located mainly within the cardiomyocyte, associated to SL, intercalated discs and T-tubules connected to the terminal cisternae of SR where excitation-contraction coupling takes place (Fig. 2) [36–39,41,57]. It has also been described associated to the Z lines [23]. Furthermore, annexin A5 is present in vascular endothelial cells, both in the microcirculation and major coronary vessels, and in the adventitia of large vessels in rat and guinea pig (Fig. 3) [41,57]. Interestingly, annexin A5 has previously been detected in specific atrial granules where atrial natriuretic peptide is stored, and suggested to play a role as mediating atrial natriuretic peptide secretion [58].

In compensated hypertrophy, expression of annexin A5 was found to be unchanged [59] whereas during the development of heart failure increased amounts of annexin A5 (1.5-fold at both the mRNA and protein levels) have been reported in the left ventricle of hypertensive guinea pigs [41] and of failing human hearts [38,46]. However, the most striking event in failing heart is the relocalization of annexin A5 from cardiomyocytes within the interstitial space. Indeed, Benevolenski et al. found that annexin A5 staining was faint and even absent from many cardiomyocytes and was concentrated in areas corresponding to fibrotic tissue (Fig. 2). However, in some areas cardiomyocytes exhibit normal annexin A5 localization [38]. In contrast with these observations, Matteo and Moravec [39] did not find such specific redistribution of annexin A5 in failing hearts but rather a disorganization of the cross-striated pattern observed in non-failing hearts. Translocation of annexin A5 from myocytes to the interstitial space has also been observed in Langendorff perfused heart [60] and in rat heart after 1 h of cardiac ischemia in an in vivo model [61]. It has not yet been demonstrated whether this translocation is related to secretion from myocytes but the early increase of annexin A5 in plasma from patients after acute myocardial infarction supported this assumption [62]. Furthermore, recent findings on apoptosis have confirmed that translocation and externalization of annexin A5 could occur in cardiomyocytes [63]. This externalization could correspond to a proapoptotic effect of annexin A5 linked to Ca2+ channel activity, as in the case of chondrocytes [21,64]. It is worth noting that redistribution of annexin A5 in the myocardium occurs in pathophysiological conditions (ischemia, ischemia–reperfusion, heart failure) where Ca2+ is elevated and where apoptosis has been reported [65]. In line with these data, studies using a benzothiazepine derivative (K201 or JTV519) reported binding of this drug to annexin A5, and a protective effect in ischemia–reperfusion [66–68]. However, it is not clear whether protection was effected through an inhibitory effect on the Ca2+ channel activity of annexin A5 or regulation of other additional mechanisms including the NCX [69–71]. In line with this last assumption, Camors et al. found that annexin A5 was forming a complex with NCX suggesting a role for this annexin as a regulatory factor of Ca2+-handling proteins. Formation of this complex was demonstrated in both non-failing and failing human hearts but there is so far no clear evidence of modulation of activity that could be accounted for by annexin A5 binding to NCX [72].

In summary, these results in myocardium showing a redistribution (at least disorganization) limited to the ischemic and failing heart, a proapoptotic effect and a protective effect through inhibition of endogenous annexin A5 suggest possible annexin A5 involvement in Ca2+ handling (either directly or by binding NCX) and in the development of heart failure.

3.4. Annexin A6
Although annexin A6 was one of the first annexins thought to regulate Ca2+ handling, its role in myocardium is still largely unknown. Annexin A6, like annexin A5, is known to form an active Ca2+ channel [18] and has been involved in exocytosis and release of atrial natriuretic peptide from atrial granules [58]. Regulation by annexin A6 of membrane trafficking and endocytosis has been recently reported by Grewal et al. [73]. By investigating the potential role of annexins in the regulation of sarcolemmal organization of smooth muscle cells, Babiychuk et al. showed a relocation of annexin A6 from the cytoplasm to the plasmalemma after stimulation. This relocation led to a reorganization of the membrane proteins and particularly of the caveolae in an active cytoskeleton-membrane complex [24]. In line with a rapid translocation of annexins related to changes in [Ca2+]i, Draeger et al. [27] demonstrated in skeletal muscle that annexin A6, which is diffusely distributed within the cytoplasm in relaxed fibers, is found in the SL and transverse tubular system during contraction.

As shown in Figs. 2 and 3Go, annexin A6 in the heart has been localized in the cytosol, sarcolemma, T-tubules and intercalated discs of cardiomyocytes from numerous species and in endothelial and smooth muscle cells [36–39,41]. Annexin A6 is the most abundant annexin in the myocardium (13.5 µg/mg of total proteins of human heart). However, it is not clear whether the protein level of annexin A6 is modified in heart disease. It has been reported to be increased at the onset of heart failure in guinea pig [41] and to be slightly increased [38] or unchanged [39] in homogenates from failing human hearts. On the contrary, Song et al. [46] reported a 46% decrease in failing human heart but this decrease only concerned annexin A6 present in EGTA extracts. Moreover, no substantial differences in localization were observed [38,39].

Finally, a potential role for annexin A6 in heart muscle will be examined. The first study supporting a modulatory effect of annexin A6 showed increases in the probability of opening and mean open time of SR Ca2+ release channels reconstituted into planar bilayers when annexin A6 was added to the luminal side of SR [74]. However, the potential effect of annexin A6 on RyR2 activity in vivo has never been investigated. It has been shown that transgenic mice overexpressing annexin A6 presented alterations in contractile mechanics and Ca2+ homeostasis [9]. These animals had dilated cardiomyopathy, a reduced frequency-dependent percentage of shortening, decreased rates of contraction and relaxation, lower basal levels of intracellular free Ca2+ and a reduced rise in the peak Ca2+ transient. The effect seemed to be due in part to enhanced NCX activity. In contrast, in annexin A6 null-mutant mice Song et al. [75] reported an unchanged basal level of Ca2+, an increased rate of Ca2+ removal in myocytes and enhanced contractility. In summary, these last studies suggest that annexin A6 has an indirect negative inotropic effect on myocardium. However, further experimental work is required to determine the target of annexin A6 and its regulatory function.

3.5. Annexin A7
Annexin A7 (also called synexin) was first described by Creutz et al. in 1978 (for review, see Ref. [76]). Purified as a protein able to aggregate and promote the fusion of chromaffin granules in a Ca2+-dependent manner, annexin A7 has more recently been shown to have a role in exocytosis [77]. A remarkable feature of annexin A7 is its ability to form a Ca2+ channel in phospholipid bilayers and exhibit Ca2+-dependent GTPase activity regulated by protein kinase C [76,78].

Selbert et al. [79] studied annexin A7 in skeletal muscle, where it is localized in the sarcolemma and T-tubules. In the heart, the protein is expressed by the cardiomyocytes but its cellular localization has yet to be defined. Alternatively spliced, the gene of annexin A7 codes for two isoforms of 47 and 51 kDa, which differ by 22 amino acids in their N-terminal domain. In skeletal muscle, expression of the 47 kDa isoform is abolished during myoblastic differentiation whereas the 51 kDa isoform is expressed in differentiated muscle cells. In other tissue, only the 47 kDa isoform is expressed, except in heart and brain where both isoforms are present [79,80]. In muscle specimens from patients suffering from Duchenne muscular dystrophy and from the MDX mouse, Selbert et al. [81] reported a relocalization of annexin A7 from the sarcolemmal membrane to the cytosol followed by release of the protein in the extracellular space. The authors suggested that relocalization was linked to disorders in Ca2+ regulation observed in hypercontracted muscle fibers.

The first knockout of the annexin A7 gene (–/–) was performed by Srivastava et al. [82] to define the role of the protein in the control of secretion in pancreatic islets. Homozygous (–/–) mice showed a lethal phenotype induced by cerebral hemorrhage at embryonic day 10. Heterozygous annexin A7 (+/–) mice, expressing low levels of annexin A7 protein, were viable and their phenotype was associated with a substantial defect in insulin secretion and, interestingly, with an alteration of Ca2+ signaling due to a reduction in IP(3) receptor expression and function. The second knockout of the annexin A7 gene was performed by Herr et al. [83] and led to viable animals with no apparent defects. Cardiomyocytes isolated from early embryos displayed normal Ca2+ homeostasis and excitation-contraction coupling, whereas adult cardiomyocytes showed a decrease in the cell shortening–frequency relationship at high frequencies. The authors suggested that the discrepancy between the KO performed by Srivastava et al. [82] could be due to altered expression of genes near the integration site or to a different genetic background. However, these results suggest that annexin A7 might contribute to the dysregulation of intracellular Ca2+ homeostasis in adult hearts under stress conditions.

Remarkably, in chromaffin cells, Brownawell and Creutz [31] showed the formation of a complex between annexin A7 and sorcin. They suggested that the complex promotes reciprocal regulation of both proteins in a Ca2+-dependent manner. On the other hand, sorcin has been reported to interact both with the RyR2 and the L-type Ca2+ channels and it was suggested that it could act as a mediator of interchannel communication during excitation-contraction coupling [3,84]. While the role of annexin A7 in the heart is still unclear, recent publications suggested its direct involvement in Ca2+ handling and/or in macromolecular complexes involved in Ca2+ homeostasis.


   4. Conclusion
Top
 Abstract
 1. Introduction
 2. Overview of annexin...
 3. Myocardial annexins
 4. Conclusion
Acknowledgment
 References
 
In conclusion, the studies reviewed suggest that different annexins–and mainly annexins A5, A6 and A7–could be involved in the regulation of Ca2+ handling in cardiomyocytes. In favor of such regulation are their presence in the dyadic cleft and their co-localization with Ca2+-handling proteins. Experimental results attesting to such regulatory functions are (1) the Ca2+ channel formed by annexin A5, its role during apoptosis and the protective effect of annexin A5 inhibitor JV 509 on ischemia–reperfusion injury, (2) the dilated cardiomyopathy related to annexin A6 overexpression, and (3) the decrease in frequency-induced cell shortening in annexin A7 deficient mice. However, whether these effects were directly related to the formation of Ca2+ channels (suggested for annexin A5) or/and to association and regulation of Ca2+-handling protein(s) in multimolecular complexes has yet to be investigated. Given the homology of annexins, it might be thought that one annexin could substitute for another, but knockout studies showing quite different regulations argue for a specific role of each annexin in the myocardium.

Except for genetic models, few studies have focused on annexins and Ca2+ signaling in the heart. Annexins A5, A6 and A7 are abundant proteins of the myocardium and differences in their expression and/or localization in physiopathological conditions suggest that they might play a role in cardiac diseases. To date, annexin A2 has been associated with acute promyelocytic leukaemia and annexin A5 with antiphospholipid syndrome and preeclampsia during pregnancy, leading to the term "annexinopathies" [85]. However, annexinopathies have not yet been evidenced in heart. Finally, changes in the cellular localization and expression of annexins in the failing heart suggest a possible function for annexins in altered electromechanical coupling and Ca2+ homeostasis, but the precise role of each annexin needs to be further investigated.


   Acknowledgment
Top
 Abstract
 1. Introduction
 2. Overview of annexin...
 3. Myocardial annexins
 4. Conclusion
 Acknowledgment
References
 
This study was supported by grants from the French Fondation de la Recherche Médicale (to E.C.), the GRRC (to E.C.) and the MRT (to V.M.).


   Notes
 
Time for primary review 40 days


   References
Top
 Abstract
 1. Introduction
 2. Overview of annexin...
 3. Myocardial annexins
 4. Conclusion
 Acknowledgment
 References
 

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