Calcium signaling in diabetic cardiomyocytes

Cell Calcium 56 (2014) 372–380

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Cell Calcium journal homepage: www.elsevier.com/locate/ceca

Review

Calcium signaling in diabetic cardiomyocytes Laetitia Pereira a , Gema Ruiz-Hurtado b,c , Angélica Rueda d , Jean-Jacques Mercadier e,f , Jean-Pierre Benitah e , Ana María Gómez e,∗ a

Department of Pharmacology, University of California Davis, Davis, CA 95616, USA Unidad de Hipertensión, Instituto de Investigación i+12, Hospital Universitario 12 de Octubre, Madrid, Spain Instituto Pluridisciplinar, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain d Departamento de Bioquímica, Cinvestav-IPN, México, DF, Mexico e Inserm, UMR S769, Faculté de Pharmacie, Université Paris Sud, Labex LERMIT, DHU TORINO, Châtenay-Malabry, France f Université Paris Diderot – Sorbonne Paris Cité, Assistance Publique – Hôpitaux de Paris (AP-HP), France b c

a r t i c l e

i n f o

Article history: Available online 17 August 2014 Keywords: Diabetes Calcium Ryanodine receptors Calcium sparks Sex related differences

a b s t r a c t Diabetes mellitus is one of the most common medical conditions. It is associated to medical complications in numerous organs and tissues, of which the heart is one of the most important and most prevalent organs affected by this disease. In fact, cardiovascular complications are the most common cause of death among diabetic patients. At the end of the 19th century, the weakness of the heart in diabetes was noted as part of the general muscular weakness that exists in that disease. However, it was only in the eighties that diabetic cardiomyopathy was recognized, which comprises structural and functional abnormalities in the myocardium in diabetic patients even in the absence of coronary artery disease or hypertension. This disorder has been associated with both type 1 and type 2 diabetes, and is characterized by earlyonset diastolic dysfunction and late-onset systolic dysfunction, in which alteration in Ca2+ signaling is of major importance, since it controls not only contraction, but also excitability (and therefore is involved in rhythmic disorder), enzymatic activity, and gene transcription. Here we attempt to give a brief overview of Ca2+ fluxes alteration reported on diabetes, and provide some new data on differential modulation of Ca2+ handling alteration in males and females type 2 diabetic mice to promote further research. Due to space limitations, we apologize for those authors whose important work is not cited. © 2014 Elsevier Ltd. All rights reserved.

1. Introduction: diabetic cardiomyopathy Diabetes mellitus is a chronic disease by which the impossibility to maintain normal glucose homeostasis leads to chronic hyperglycemia. Two main very different pathophysiological mechanisms lead to this inability to maintain normal plasma glucose concentration. In type 1 diabetes (T1D), also called juvenile diabetes or insulin-dependent diabetes, an autoimmune process directed against insulin-secreting ␤ cells of pancreatic islets, probably triggered by environmental factors such as a viral infection occurring on a favoring genetic background, leads to decreased insulin secretion when 80–90% of ␤ cells are destroyed. Due to the overall increase in autoimmune diseases, its incidence increases by 3 to 4% each year [1]. Pathophysiology of type 2 diabetes (T2D) is more

∗ Corresponding author at: Inserm U769, Faculté de Pharmacie, Université Paris Sud, 92296 Châtenay-Malabry, France. Tel.: +33 146 83 57 18; fax: +33 146 83 54 75. E-mail address: [email protected] (A.M. Gómez). http://dx.doi.org/10.1016/j.ceca.2014.08.004 0143-4160/© 2014 Elsevier Ltd. All rights reserved.

complex and comprises itself two main mechanisms: a resistance of the peripheral tissues to the action of insulin that results in increased insulin needs to maintain normal glycemia, and an alteration in insulin secretion that does not allow ␤ cells to fulfill the increased needs. Resistance to insulin action in T2D is also favored by genetic susceptibility but also sociological and environmental factors such as life style with an excess of poor quality diet and lack of sufficient physical activity resulting in obesity often associated with hypertension. Such obesity realizes currently a serious epidemic worldwide with a current prevalence of approximately 400 million (8.3% of world population) and an anticipated prevalence of approximately 600 million (8.9%) in 2035 [2]. Untreated or poorly controlled diabetes is a serious threat for most tissues and organs of the body. Together with other risk factors, it contributes to the development of atherosclerosis of large arteries. More specific of diabetes is the damage caused to microvessels such as those of the retina or kidneys. There have been controversies regarding the existence of a specific diabetic cardiomyopathy (DCM), independent from coronary artery disease, as this concept has emerged mainly from experimental studies [3].

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Nevertheless, a specific type of cardiomyopathy was first described 40 years ago based on the pathologic observations of hypertrophied and fibrotic hearts in patients with heart failure (HF) in the absence of coronary artery disease or any other pathophysiological process susceptible to explain HF [4]. This initial study has been confirmed and extended by others and DCM is now defined as the existence of LV dysfunction in diabetic patients lacking other potential etiological condition. The mechanisms underlying DCM seem to involve a cardiac remodeling associating LV hypertrophy with increased myocardial collagen and lipid content metabolic changes and alteration in Ca2+ signaling in cardiac myocytes [5–8]. However, the multifactorial etiology of the disease contributes to its complexity and cellular and molecular dysfunctions occurring at the level of cardiac myocytes are not yet fully understood. In this review we will focus on Ca2+ signaling alterations and how they compromise contraction and relaxation of the diabetic heart. 2. Ca2+ signaling in cardiomyocytes 2.1. Ca2+ -induced Ca2+ -release (CICR) Ca2+ plays a fundamental role in heart function by activating contraction and regulating gene transcription, metabolism and cell death [9]. Cardiac contractility is triggered by Ca2+ -induced Ca2+ -release (CICR) mechanism during the excitation-contraction (EC) coupling [10]. The EC coupling is described as follow: For each cardiac cycle, membrane depolarization, generated during the action potential, induced an initial Ca2+ signal. This initial signal is produced by the entry of Ca2+ through the sarcolemmal L type Ca2+ channels (LTCC). The resultant elevation in cytosolic [Ca2+ ]i is not enough to activate contraction. However, this Ca2+ influx is sufficient to activate the Ca2+ release channels (ryanodine receptors, RyR) located at the sarcoplasmic reticulum (SR), to amplify the initial signal and provide enough Ca2+ to activate contractile myofibrils. The close proximity between LTCC, at the transverse tubules of the sarcolemma, and the RyRs at the junctional SR confers a local control of the CICR mechanism where only the RyRs that are close to the LTCC get activated. This characteristic allows the signal to be graded, so contraction can be modulated depending on how many channels are activated, among other factors. Different expression or spatial distribution (such as TT remodeling) of one or both of these channels may underlie defects in contraction [11]. The activity of LTCC is measured by patch-clamp as a Ca2+ current (ICa ) and variations on ICa density have been found in some models of diabetic cardiomyopathy (see below). The [Ca2+ ]i variations may be analyzed, among other methods, by fluorescence techniques loading the cardiac myocytes with Ca2+ fluorescence dyes. Confocal imaging has provided a useful tool to analyze [Ca2+ ]i at the global ([Ca2+ ]i transients) and local (Ca2+ sparks) level. Ca2+ sparks were first identified by Cheng et al. as local, rapid, and brief elevations in [Ca2+ ]i [12] whereas [Ca2+ ]i transients correspond to simultaneous Ca2+ release through the RyRs in response to membrane depolarization. Since then, Ca2+ sparks have been used to measure the activity of RyRs, in normal cardiomyocytes and also some pathologic states including diabetic cardiomyopathy [13,14]. 2.2. Relaxation phase The relaxation phase is the result of the decrease in the cytosolic [Ca2+ ]i and is regulated by two main components: the SR Ca2+ pump (SERCA) and the Na+ /Ca2+ exchanger (NCX). The SERCA reduces cytosolic [Ca2+ ]i level by pumping back the Ca2+ to the SR, expending energy in the form of ATP. Its activity is tightly regulated by phospholamban (PLB), which slows down SERCA activity when unphosphorylated. In addition, the Na+ /Ca2+ exchanger (NCX)

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extrudes the Ca2+ out of the cardiomyocytes by exchanging one Ca2+ ion with 3 Na+ . The relative contribution of both systems depends on the analyzed species and may be altered in pathological states. However, other slow systems contributes to [Ca2+ ]i transient relaxation as well, but at a much limited rate: Namely the plasmalemal Ca2+ ATPase (PMCA) and the mitochondrial transport. The NCX is reversible and depends on [Na+ ]i and [Ca2+ ]i at both sides of the membrane, and on voltage. Thus it may also contribute to triggering Ca2+ release. Because it is electrogenic, the NCX may be involved in arrhythmia by inducing delayed after depolarization (DAD) and triggered activity in conditions of aberrant Ca2+ release during diastole. 3. Ca2+ signaling in type 1 diabetes Type 1 diabetes (T1D) experimental models, such as the streptozotocin (STZ)-induced diabetic (mouse or rat) [15] and the insulin-deficient diabetic mice heterozygous C57BL/6 for the Ins2Akita mutation (Akita mice) [16] are similar to human T1D. They display cardiomyopathy with significant systolic and diastolic dysfunction leading to heart failure (HF). T1D contractile dysfunction is characterized by a decrease in fractional shortening [17,18], ejection fraction [19], and heart rate [20]. However, unlike other heart failure models, they do not always develop cardiac hypertrophy [20,21], heart weight change [18,22] or cardiac atrophy [23]. This particularity is possibly due to apoptosis [24] and/or depression of cardiomyocyte volume [25]. Moreover, T1D show alterations of the left ventricular rate of systolic pressure (+dP/dt), the rate of decline (−dP/dt) with abnormal time to relaxation [20,22,23] suggesting that contractile dysfunction of T1D is mainly due to intrinsic factors within the diabetic heart. Though, an increase in the amplitude of shortening but with prolonged time to peak has been also described by other authors [26]. These discrepancies could result from STZ dose used which highly influence the severity of T1D, its stage of development and also the age of onset of diabetes. In either case, it is commonly admitted that, changes in contractile function in T1D are the reflection of a deep alteration of Ca2+ signaling at different levels: (i) Ca2+ entry/influx; (ii) intracellular Ca2+ cycling; (iii) Ca2+ extrusion/efflux. 3.1. Ca2+ entry/influx Several studies showed normal ICa density but prolonged action potential duration due to down regulation of potassium currents. However, different studies and models have provided conflicting data: Increased PH200-110, a dihydropyridine derivative, binding sites in diabetic cardiac SL membrane [27], or decreased nitrendipine binding sites with increased affinity were observed in diabetic cardiac membranes [28]. Net influx of Ca2+ was reported to be significantly reduced in chronic 4–8 weeks diabetic rat myocardium [29]. Although some studies have shown normal function of LTCC [18,20,30], others have established a reduction in LTCC protein expression with the consequent decrease in ICa density in T1D myocytes compared with control myocytes [17,28,31,32]. Besides LTCC expression, the biophysical properties of the LTCCs are altered. ICa shows altered voltage dependence with the steady-state activation and inactivation curve shifted toward more positive potentials in diabetic compared with nondiabetic myocytes [17]. These changes in the biophysical properties, together with a reduced membrane expression of LTCCs [28], may suggest that only a smaller proportion of the LTCCs are available to open during each action potential, thus reducing the net influx of Ca2+ though LTCCs in T1D myocytes [17]. However, some studies have suggested that the reduced Ca2+ entry together with the inability of cardiomyocyte to utilize

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glucose may be actually beneficial under stress conditions, such as mild or severe ischemia [33–35]. Although controversial, it has been documented that diabetic hearts are protected from ischemia/reperfusion (IR) injury from very early stages of diabetes (i.e., 48 h after alloxan or STZ injection) [33–35]. This protection might be related to a reduced Ca2+ influx during reperfusion via LTCCs, the reverse-mode of Na+ /Ca2+ exchanger and/or other forms of voltage-independent Ca2+ entry. At least the former two Ca2+ transport systems are depressed in the diabetic heart [28,34]. In addition to Ca2+ influx through LTCC, voltage-independent Ca2+ entry might co-exist, mediated by (1) the store-operated channels (SOCs); (2) the receptor-operated channels (ROCs); (3) the ligand-gated ion channels (LGCs); and (4) the stretch-activated channels (SACs). Due to the practically neglected participation of all above mentioned channels in reloading SR Ca2+ stores of cardiomyocytes, their physiological role in heart function has only started to be explored very recently. Store-operated Ca2+ entry (SOCE) is present in neonatal and adult rat ventricular myocytes, is activated by IP3 -induced store depletion and is required for the onset of hypertrophic signaling pathways [36,37]. This Ca2+ signaling pathway is mediated by the stromal-interacting molecule (STIM), the Ca2+ release-activated Ca2+ modulator (ORAI) and some members of the transient receptor potential (TRP) superfamily. In normal adult rat cardiomyocytes, STIM1 and ORAI1 co-localize with SERCA and RyRs, supporting a key role of former channels in SOCE. Conditions such as hyperglycemia that increase STIM1 post-translational modification by O-linked N-acetylglucosamine, attenuate SOCE in neonatal cardiomyocytes and could depress hypertrophic signaling, in addition to afford some protection against the reperfusion-induced arrhythmias [36,37]; however, this altered Ca2+ signaling pathway has not been studied in detail using adult diabetic cardiomyocytes yet, or more important in resident cardiac stem cells of diabetic hearts where SOCE could have a prominent role. TRP superfamily is among those channels mediating voltageindependent Ca2+ entry in the heart. All TRP channels are permeable to Ca2+ , but only few are highly Ca2+ selective [38]. Based on amino acid sequence homology, the mammalian TRP superfamily is divided in 6 subfamilies: canonical (TRPC), vanilloid (TRPV), melastatin (TRPM), polycistin (TRPP), mucolipin (TRPML) and ankyrin (TRPA) [38]. Expression of TRPC1-7, TRPV1, TRPV4, TRPP1, TRPP2,TRPM2-4 and TRPM7 has been found in whole heart tissue [39–43], and isolated cardiomyocytes [39]; but for several TRP channels a more detailed analysis needs to be done in order to determine specifically in what kind of cardiac cell subtypes are those channels expressed. Regardless of general TRPs cellular localization and precise function in the cardiovascular system, which has been reviewed nicely [39,44,45], a recent publication has reported that in STZ-induced T1D heart, the TRPC6 expression is increased in the whole tissue, while no discernible change in the aorta was observed [41]. The TRPC6 channel appears to be activated by mechanical stretch [39], promoting LTCC activation, so that such a coupling might be altered in the diabetic heart. In the case of TRPV1, which is mainly expressed at cardiac sensory neurons and activates nociceptors to detect tissue ischemia [39], its expression has been found diminished in diabetes [40]. In this sense, alteration of TRPV1 may impair post-ischemic recovery of diabetic mouse hearts [46]. Finally, very recent data argue in favor of TRPM2 participation in the protection of hearts against I/R injury via reducing ROS generation and increasing ROS scavenging capability in adult cardiomyocytes, by maintaining normal mitochondrial function [43]. Since TRPM2 also participates in the regulation of glucose uptake and insulin signaling in normal cardiac cells, and that both activities are dampened under the diabetic condition, thus, one might hypothesize that TRPM2 channel expression could be increased in the diabetic heart. However, no direct

evidences have involved TRM2 channels in the pathophysiology of the T1D heart yet. 3.2. Intracellular Ca2+ cycling There is a broad consensus about the involvement of [Ca2+ ]i cycling alteration in the contractile dysfunction of the diabetic heart. Indeed, several studies described alterations in [Ca2+ ]i transients in T1D myocytes [18–20,25,47]. In T1D, the amplitude of [Ca2+ ]i transients is significantly decreased as well as systolic rate of Ca2+ rise and decay [18,19,22]. In addition, the intracellular [Ca2+ ]i transients in cardiomyocytes from T1D animals are non-uniform [18,47]. Thus, after electrical field stimulation of diabetic ventricular myocytes a dyssynchronous intracellular Ca2+ release can be observed and abnormal diastolic Ca2+ waves appear, especially when the stimulation frequency is enhanced. In some models, a reduction in the amplitude and kinetics of [Ca2+ ]i transients can also be observed without any reduction in the Ca2+ influx through LTCCs [20]. This clearly supports the idea that the contractile dysfunction observed in T1D myocytes is linked to alteration in the intracellular Ca2+ cycling. The prolonged [Ca2+ ]i transient decay is a consequence of an impairment of SR Ca2+ reuptake during the relaxation phase, causing up to a 50% reduction in intra-SR Ca2+ stores (SR Ca2+ load) observed by caffeine-induced [Ca2+ ]i transients in T1D animals [23,48]. The significant prolongation in the decay time constant of [Ca2+ ]i transients (commonly referred to as Tau or ␶) results in longer time durations required for cytosolic Ca2+ sequestration into SR after each twitch, leading to slower relaxation of cardiac myocytes and diastolic dysfunction observed in T1D myocytes. Several reports have shown in STZ-induced diabetes that the prolongation in [Ca2+ ]i transient decay is caused by a defective SERCA pump function, in part due to reduced protein expression [14,20,49]. In fact, a landmark of the diabetic condition is the overall augmented rate of protein degradation, and SR Ca2+ cycling proteins are not excluded of this fate. Depressed SR function in diabetic rat cardiomyocytes is associated to decreased levels of SR Ca2+ cycling proteins, mainly, SERCA and RyR [20,14,50–53]. Nevertheless, some discrepancies are found in the time required after STZ injection for detecting a significant reduction of total protein levels. While some researchers have found a significant reduction of RyR expression at week 4–5 post STZ-injection [14,54,55], others have found a reduction of total RyR only after 8 weeks post-injection or even longer [20,56,57], or postulating no decrease at all [18]. On the other hand, alterations in function and expression of cardiac SERCA pump are more consistent. SERCA pump dysfunction is already established at early stages of T1D, its reduction being more evident after 4 weeks of STZ-injection [14,20,50–53,57]. More discrepancies are found in the reports of PLB, mentioning no-change [50,53], diminished [52], or augmented levels [20,51] of total PLB, which finally could contribute to further modify SERCA activity. Interestingly, no changes of Calsequestrin expression levels have been reported in T1D hearts [20,51,55]. Ca2+ sparks are the building block of [Ca2+ ]i transients. Thus, some groups have been interested in studying the characteristic of the local release events in the T1D diabetic heart. Yaras et al., reported for the first time that Ca2+ sparks from STZ-induced diabetic cardiomyocytes had slower temporal kinetics (i.e., prolonged rise and decay times) but higher frequency when compared with control cells, pointing out to the participation of a leaky SR in diabetic cardiomyopathy [14]. These effects were less pronounced in female diabetic animals [58] and were accompanied by a hyperphosphorylation of the RyR and decreased expression of the FKBP12.6 protein [14,58]. These data are in agreement with the later findings of Bidase’s group [18]. Importantly, Ca2+ spark properties are altered as diabetes progresses [55]. Nevertheless,

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considering that luminal Ca2+ modulates RyR open probability (P0 ) and consequently Ca2+ spark frequency; a higher Ca2+ spark frequency in diabetic cardiomyocytes could be incompatible with the diminished SR Ca2+ load and expression of RyRs. To overcome this issue, it was argued that a reduced expression of the FK506 binding protein (FKBP12.6, part of RyR macromolecular complex, which stabilizes RyR in the closed state) and an increased phosphorylation of RyR at one of the PKA consensus site (Ser-2808 in human heart, Ser-2807 in mouse) in the STZ-induced T1D hearts, account for the rise in Ca2+ spark frequency [14]. Although some studies have pointed to RyR phosphorylation at the PKA site, as involved in cardiomyocytes dysfunction in cardiac diseases, many experimental data have shown that PKA-mediated RyR hyperphosphorylation at Ser-2808 does not significantly modify RyR in situ activity [59–66]. More compelling evidence argued in favor of a gain-of-function of RyR due to other deleterious post-translational modifications [67]. For instance, diabetic heart tissue has elevated levels of carbonyland AGE-adducts of RyR and SERCA pump that could account for the dysfunctional proteins in the diabetic condition [47,68]. In addition, RyR isolated from STZ-diabetic hearts and incorporated into lipid bilayers have shown a 4 fold increase in the mean open probability (Po) at 1 ␮mol/L of cis Ca2+ , with a 20% reduction in mean current amplitude [67]. The gain of RyR function expressed in STZ/T1D hearts was also explained by the enhanced responsiveness of those channels to ATP, Ca2+ , and cADPR, concomitant with a diminished inhibition by Mg2+ . This gain-of-function of RyR was not associated with increased RyR phosphorylation at Ser2808 and Ser2814 (the CaMKII phosphorylation site in human heart, corresponding Ser2813 in mouse heart), or oxidation of hyper-reactive cysteine residues [67]. One might hypothesize that RyR gain-of-function in diabetes might be a mechanism to compensate for the reduced SR Ca2+ loading and RyR diminished expression, so that RyRs could still be able to open even with less Ca2+ stored. However, opposite results have been reported by Zhao et al. [55] in T1D cardiomyocytes from STZ-injected rats, Ca2+ spark frequency being significantly decreased 4 weeks post-injection; these findings are in agreement with similar data in type-2 diabetic cardiomyocytes [13]. The molecular bases of these discrepancies are still unknown. In order to explain these discrepancies, it is important to consider that diastolic Ca2+ levels can modify RyR in situ activity. In this regard, both elevated or no changes in diastolic [Ca2+ ]i levels have been reported in T1D cardiomyocytes [20,49,69] and the origin of this discrepancy has not been analyzed in more detail. Finally, several strategies have been used to restore SERCA pump and RyR functionality; so far, the best approach has been the re-introduction of insulin to those animals with STZ-induced diabetes. However, angiotensin-II receptor blockade, PKC inhibition and dietary supplementation with antioxidants, among others, have been also successful.

3.3. Ca2+ extrusion/efflux The decline of [Ca2+ ]i in the presence of caffeine is referred to Ca2+ extrusion or efflux mainly through NCX, and to a lesser extent via PMCA and via Ca2+ uptake into mitochondria. NCX-dependent Ca2+ efflux is altered in T1D. Some studies have indeed shown that the expression and activity of NCX is considerably decreased in T1D rats treated with STZ [18,20]. This reduction in NCX function may contribute to the decrease in the rate of decline of [Ca2+ ]i transients observed in T1D cardiomyocytes. Opposite to STZ-T1D model, it has been observed a significant increase in NCX expression in T1D Akita mice, but without any change in NCX activity [23]. Interestingly, in this study Akita mice present a preserved systolic function despite an important depressed SERCA function and decreased SR

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Ca2+ load. Thus, it seems that overexpressed NCX can compensate to maintain adequate contractile function by increasing Ca2+ entry [23]. Moreover, it has also been observed a prolonged action potential duration (APD) in experimental animals with T1D supporting the increased activity of NCX in the reverse mode [31]. Ca2+ influx is also favored in T1D by APD prolongation, resulting from decrease in transient outward potassium current (Ito ) [70]. However, while AP prolongation may help contractile function, it may be deleterious by triggering arrhythmias. In fact, the slower repolarization phase of the action potential may be responsible for the longer QRS and QT intervals observed in T1D animals and patients [18,71–73]. All these important changes in the Ca2+ signaling described above are involved in the deleterious changes in cardiac contractile function in T1D conditions. 4. Ca2+ signaling in type 2 diabetes As in T1D, type 2 diabetic (T2D) cardiomyopathy is associated with defective cardiac performance characterized by cardiac contraction and relaxation dysfunction. However, unlike T1D, T2D can develop both hypertrophy and heart failure [74,75]. Even though studies in T2D are less extensive than in T1D, T2D contractile dysfunction also depends on Ca2+ signaling alteration, such as Ca2+ induced Ca2+ -released, Ca2+ extrusion/efflux and diastolic Ca2+ release. 4.1. Ca2+ -induced Ca2+ -release Striking evidences show several similarities in Ca2+ signaling alteration between T1D and T2D. Indeed, in db/db mouse, a T2D model with insulin-resistance linked to obesity, the contractile dysfunction is also driven by a significant reduction in the [Ca2+ ]i transient [5,13]. This drop in [Ca2+ ]i transient amplitude was observed in both isolated cardiac myocytes and in the perfused whole heart [13]. [Ca2+ ]i transient amplitude is directly regulated by several factors, such as Ca2+ influx by ICa , SR Ca2+ content, and RyRs (see above). We have shown, in 15 weeks old db/db mice, that the macroscopic ICa was reduced, while the single channel current (ICa ) was unaltered suggesting a decrease in LTCC channels expression rather than biophysical properties alteration of each channel [13]. Indeed, the drop in ICa density was associated with diminished expression in the pore forming subunit of the LTCC, the ␣1C [13]. Depression on LTCC density has been found by other authors in db/db mice, as well as in Zucker diabetic fatty rat (ZDF) [13,76–78]. Interestingly, in the young non hypertrophic Goto-Kakizaki sucrose feed model, expression of Cacnac1, Cacnb1 and Cacnb2 (genes encoding for the ␣1 , ␤1 and ␤2 subunits of LTCC) were not altered [79] suggesting that ICa,L downregulation is a result of maladaptive remodeling in the onset of diabetes. The downregulation of ICa,L seems to be mediated, at least in db/db model, by a decrease of PI3K/PIP3/Akt/PKC signaling cascade [78] which highlights the impact of insulin-resistance on the overall cardiac function. Indeed, depressed ICa,L contributes to contractile dysfunction either directly, by triggering smaller Ca2+ release, or indirectly, through drop of SR Ca2+ content (or SR Ca2+ load), because ICa serves to both, trigger Ca2+ release and reload the SR with Ca2+ [80]. In db/db mice, SR Ca2+ content is significantly reduced and associated to lower SERCA activity [13]. Even though SERCA expression may not be altered in this model, an increase in the PLB expression may underlie the reduced SERCA activity [5], which together with an increase in Ca2+ extrusion through the NCX contributes to lowering SR Ca2+ load [13]. However, ventricular tissue from another T2D model, glucose intolerant rats, showed a decreased SERCA mRNA level [81]. Similar results were observed in genetically obese fa/fa [82,83] and Otsuka Long Evans Tokushima Fatty rat [83].

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Fig. 1. RyR2 expression is depressed in male db/db hearts, with normal phosphorylation at the CaMKII site, but higher at the PKA site, correlated with higher Ca2+ spark amplitude. (A) Ca2+ spark frequency measured in permeabilized ventricular cardiac myocytes from control male mouse hearts (+/+, white bar, n = 199 Ca2+ sparks) and type 2 diabetic mice (db/db, green bar, n = 428 Ca2+ sparks). (B) Western blot example (in top) and average expression (below) of total RyR (n = 7 hearts in each case, colors as in A). (C) Same as in B but for RyR phosphorylated at S2813. (D) Ratio of S2813 phosphorylated by the total RyR. For each blot, the same sample was normalized. (E) Like in (D), but for S2807 in 8 hearts of each group. *p < 0.05.

The differences between these studies may depend on severity and duration of diabetes. For example, at an early stage of T2D (ZDF rat), SERCA expression is increased and associated with an elevation of SR Ca2+ load [84]. 4.2. Diastolic Ca2+ release Few studies reported a compromised function and expression of RyR in T2D cardiomyopathy [13]. We found that the frequency of diastolic Ca2+ sparks is significantly decreased in permeabilized cardiac myocytes from male db/db mice, but with higher amplitude (Fig. 1A). The depression in RyRs activity is linked to diminished RyR expression in male db/db mice measured by ryanodine binding [13]. However, few other studies did not observe changes in RyRs expression [5,86]. The Ca2+ spark amplitude was increased in male

db/db mice (Fig. 1A), and the total amount of RyR protein, measured by western blot, was depressed (Fig. 1B), consistent with previous binding data [13]. The level of RyR phosphorylation at Ser2813 (CaMKII site in this specie) is depressed (Fig. 1C), in parallel to the depression on RyR expression, thus the relative fraction of phosphorylated RyR at Ser-2813 was not altered in male db/db mice hearts (Fig. 1D). However, RyR phosphorylation at PKA site (serine 2807 in the mouse) was increased (Fig. 1E). Interestingly, data taken at the same age (same diabetic state) in db/db female mice, which show a similar depression in the [Ca2+ ]i transient and in ICa density (data not shown), differed at the Ca2+ spark characteristics and RyR level to male db/db. Ca2+ sparks in female db/db cardiomyocytes were of higher amplitude (Fig. 2A), but the total amount of RyR protein was unaltered (Fig. 2B). RyR phosphorylation at the CaMKII site was reduced (Fig. 2C and D), whereas phosphorylation at PKA

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Fig. 2. RyR2 expression is normal in female db/db hearts, with higher phosphorylation at the CaMKII site, but depressed at the PKA site, correlated with smaller Ca2+ spark amplitude. (A) Ca2+ spark frequency measured in permeabilized ventricular cardiac myocytes from control male mouse hearts (+/+, white bar, n = 676 Ca2+ sparks) and type 2 diabetic mice (db/db, red bar, n = 190 Ca2+ sparks). (B) Western blot example (in top) and average expression (below) of total RyR (n = 4 hearts in each case, colors as in A). (C) Same as in B but for RyR phosphorylated at S2813. (D) Ratio of S2813 phosphorylated by the total RyR. For each blot, the same sample was normalized. (E) Like in (D), but for S2807 in 3 hearts of each group. *p < 0.05.

site was not affected (Fig. 2E). Thus, the smaller [Ca2+ ]i transient could be produced by fewer Ca2+ sparks in male db/db mice, or by same number of Ca2+ sparks but with lower amplitude in female db/db mice. In addition, RyR activity can also be regulated during acute hyperglycemia. Hyperglycemia leads to O-Glc-NAcylation of proteins such as CaMKII which plays a key role in the regulation of excitation-contraction coupling. A recent work in cardiomyocytes showed that acute increase of glucose or O-linked N-acetylglucosamine is directly responsible for CaMKII-dependent

diastolic SR Ca2+ leak from the RyRs leading to consequent SR Ca2+ load depletion [87]. This phenomenon can play a major role in the pre-diabetic or early stage of diabetes, when plasma glucose is higher than normal even if not yet maintained, and participate in the development of the diabetic cardiomyopathy. This is consistent with the increase of SR Ca2+ leak observed in different early stage of diabetes. Interestingly, overexpressing sorcin, a protein that binds and inhibits RyR [88], improves contractile function in db/db mice [89].

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Finally, abnormal excitation-contraction coupling alteration reduced Ca2+ availability leading to depressed contractile function. However, in addition to Ca2+ signaling alterations, contractile dysfunction can also result from alteration in myofilaments sensitivity to Ca2+ . This is shown in Goto-Kakizaki rat model where time course of myocyte shortening is prolonged and associated with both, a decrease in [Ca2+ ]i transient and a reduction in myofilament Ca2+ sensitivity [90].

[8] [9] [10] [11]

5. Concluding remarks

[12]

Cardiac dysfunction in diabetes that occurs independently of coronary artery disease and hypertension is now ascribed as the diabetic cardiomyopathy (DCM), associated with both T1D and T2D. Since intracellular Ca2+ is a major regulator of cardiac contractility, impairment of cardiac Ca2+ homeostasis is one of the hypothesis that have been proposed to be part of the pathogenesis of DCM, among several others, including autonomic dysfunction, metabolic derangements (notably oxidative stress), alteration in structural proteins, and interstitial fibrosis, which are not necessarily independent of each other. At the cardiomyocyte level, the action potential is prolonged and Ca2+ efflux is slowed, resulting in slowed myocyte shortening and lengthening. Sarcoplasmic reticulum calcium ATPase and NCX expression and function are decreased, leading to disturbances in Ca2+ handling. Calcium uptake, binding to the sarcolemma, and intake by myofibrillar calcium-ATPase activity are all decreased in the diabetic heart. An important question that remains to be solved is why those alterations are specific to diabetes (T1D and/or T2D vs HF), and whether the alterations are different in males than females, in order to develop personalized treatment strategies.

[13]

[14]

[15]

[16]

[17]

[18]

[19]

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Funding Inserm, ECOS Nord (M13S01, to J.P.B. and A.R.), Agence Nationale de la Recherche (ANR-13-BSV1-0023-01), SEP-ConacytAnuies (A.R.), Fondation pour la recherche médicale (Programme cardiovasculaire 2011), CORDDIM (to A.M.G.), American Heart Association Post-doctoral Fellowship (to L.P.), Fundación Mutua ˜ y Fundación Eugenio Rodriguez Pascual (to G.R.-H.). G.R.Madrilena H. is funded by the Ministerio de Economía y Competitividad in the Juan de la Cierva postdoctoral program from Spain.

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