Advanced glycation end product cross-link breaker attenuates diabetes-induced cardiac dysfunction by improving sarcoplasmic reticulum calcium handling (original) (raw)
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Advanced Glycation Endproduct-Induced Calcium Handling Impairment in Mouse Cardiac Myocytes
Journal of Molecular and Cellular Cardiology, 2002
Long-standing diabetes causes cardiovascular complications including direct cardiac muscle weakening known as diabetic cardiomyopathy. This is characterized by disturbances in both cardiac contraction and relaxation, which are maintained by calcium homeostasis in cardiac cells. Our recent in vitro and in vivo studies have shown that advanced glycation endproducts (AGE) account for diabetic vasculopathy through their engagement of the receptor for AGE (RAGE). Here we show that AGE and RAGE may directly affect the myocardial Ca 2 homeostasis. We created transgenic mice that overexpressed human RAGE in the heart and analyzed the Ca 2 transients in cultivated cardiac myocytes (CM) from the RAGE-transgenic and non-transgenic control fetuses. RAGE overexpression was found to reduce the systolic and diastolic intracellular calcium concentration ([Ca 2 ] i ). Exposure to AGE caused a signi®cant prolongation of the decay time of [Ca 2 ] i in CM from control mice, and this response was augmented in CM from the RAGE transgenic mice. The results suggest that the AGE and RAGE could play an active role in the development of diabetes-induced cardiac dysfunction. # 2002 Published by Elsevier Science Ltd.
Defective intracellular Ca 2+ signaling contributes to cardiomyopathy in Type 1 diabetic rats
American Journal of Physiology - Heart and Circulatory Physiology, 2002
The goal of the study was to determine whether defects in intracellular Ca2+ signaling contribute to cardiomyopathy in streptozotocin (STZ)-induced diabetic rats. Depression in cardiac systolic and diastolic function was traced from live diabetic rats to isolated individual myocytes. The depression in contraction and relaxation in myocytes was found in parallel with depression in the rise and decline of intracellular free Ca2+ concentration ([Ca2+]i). The sarcoplasmic reticulum (SR) Ca2+ store and rates of Ca2+ release and resequestration into SR were depressed in diabetic rat myocytes. The rate of Ca2+ efflux via sarcolemmal Na+/Ca2+ exchanger was also depressed. However, there was no change in the voltage-dependent L-type Ca2+ channel current that triggers Ca2+ release from the SR. The depression in SR function was associated with decreased SR Ca2+-ATPase and ryanodine receptor proteins and increased total and nonphosphorylated phospholamban proteins. The depression of Na+/Ca2+ ex...
Sarcoplasmic Ca2+ release is prolonged in nonfailing myocardium of diabetic patients
Molecular and Cellular Biochemistry, 2008
Background Asymptomatic diabetic patients have a high incidence of clinically unrecognized left ventricular dysfunction with an abnormal cardiac response to exercise. We, therefore, examined subclinical defects in the contraction-relaxation cycle and intracellular Ca 2+ regulation in myocardium of asymptomatic type 2 diabetic patients. Methods Alterations in the dynamics of the intracellular Ca 2+ transient and contractility were recorded in right atrial myocardium of type 2 diabetic patients and nondiabetic control tissue loaded with fura-2. In order to gain an insight into mechanisms underlying the altered Ca 2+ handling in diabetic myocardium levels of mRNA, protein expression and phosphorylation of key proteins in sarcoplasmic Ca 2+ handling were determined. Results In isolated atrial trabeculae of diabetic myocardium the rise of systolic Ca 2+ was significantly prolonged, but relaxation of the Ca 2+ transient was unaltered compared to control tissue. Accordingly, the levels of expression of mRNA and protein of the Ca 2+ release channel (RyR2) of the sarcoplasmic reticulum were reduced by 68 and 22%, respectively. Endogenous phosphorylation of RyR2 by protein kinases C, however, was increased by 31% in diabetic myocardium, as assessed by the back-phosphorylation technique. Levels of expression of SERCA2 and phospholamban were unaltered between both groups. Conclusions Intracellular Ca 2+ release is prolonged in non-failing myocardium of type 2 diabetic patients and this may be primarily due to a decreased expression of RyR2. This defective Ca 2+ release may represent an early stage of ventricular dysfunction in type 2 diabetes and would favor the abnormal response to exercise frequently observed in asymptomatic diabetic patients.
Dyssynchronous (non-uniform) Ca2+ release in myocytes from streptozotocin-induced diabetic rats
Journal of Molecular and Cellular Cardiology, 2007
Using biochemical/pharmacological approaches, we previously showed that type 2 ryanodine receptors (RyR2) become dysfunctional in hearts of streptozotocin-induced type 1 diabetic rats. However, the functional consequence of this observation remains incompletely understood. Here we use laser confocal microscopy to investigate whether RyR2 dysfunction during diabetes alters evoked and spontaneous Ca 2+ release from the sarcoplasmic reticulum (SR). After 7-8 weeks of diabetes, steady-state levels of RyR2 remain unchanged in hearts of male Sprague-Dawley rats, but the number of functional receptors decreased by > 37%. Interestingly, residual functional RyR2 from diabetic rat hearts exhibited increased sensitivity to Ca 2+ activation (EC 50activation decreased from 80 μM to 40 μM, peak Ca 2+ activation decreased from 425 μM to 160 μM). When field stimulated, intracellular Ca 2+ release in diabetic ventricular myocytes was dyssynchronous (non-uniform) and this was independent of L-type Ca 2+ currents. Time to peak Ca 2+ increased 3.7-fold. Diabetic myocytes also exhibited diastolic Ca 2+ release and 2-fold higher frequency of spontaneous Ca 2+ sparks, albeit at a lower amplitude. The amplitude of caffeine-releasable Ca 2+ was also lower in diabetic myocytes. RyR2 from diabetic rat hearts exhibited increased phosphorylation at Ser2809 and contained reduced levels of FKBP12.6 (calstablin2). Collectively, these data suggest that RyR2 becomes leaky during diabetes and this defect may be responsible to the reduced SR Ca 2+ load. Diastolic Ca 2+ release could also serve as a substrate for delayed after-depolarizations, contributing to the increased incidence of arrhythmias and sudden cardiac death in type 1 diabetes.
Molecular and Cellular Biochemistry, 2011
There has been a spectacular rise in the global prevalence of type 2 diabetes mellitus and cardiovascular complications are the major cause of morbidity and mortality in diabetic patients. The objective of the study was to investigate ventricular myocyte shortening, intracellular Ca 2? signalling and expression of genes encoding cardiac muscle proteins in the aged Zucker diabetic fatty (ZDF) rat. There was a fourfold elevation in non-fasting blood glucose in ZDF rats (478.43 ± 29.22 mg/dl) compared to controls (108.22 ± 2.52 mg/dl). Amplitude of shortening, time to peak (TPK) and time to half (THALF) relaxation of shortening were unaltered in ZDF myocytes compared to age-matched controls. Amplitude and THALF decay of the Ca 2? transient were unaltered; however, TPK Ca 2? transient was prolonged in ZDF myocytes (70.0 ± 3.2 ms) compared to controls (58.4 ± 2.3 ms). Amplitude of the L-type Ca 2? current was reduced across a wide range of test potentials (-30 to ?40 mV) in ZDF myocytes compared to controls. Sarcoplasmic reticulum Ca 2? content was unaltered in ZDF myocytes compared to controls. Expression of genes encoding cardiac muscle proteins, membrane Ca 2? channels, and cell membrane ion transport and intracellular Ca 2? transport proteins were variously altered. Myh6, Tnnt2, Cacna2d3, Slc9a1, and Atp2a2 were downregulated while Myl2, Cacna1g, Cacna1h, and Atp2a1 were upregulated in ZDF ventricle compared to controls. The results of this study have demonstrated that preserved ventricular myocyte shortening is associated with altered mechanisms of Ca 2? transport and a changing pattern of genes encoding a variety of Ca 2? signalling and cardiac muscle proteins in aged ZDF rat. Keywords Zucker diabetic fatty rat Á Type 2 diabetes mellitus Á Ventricular myocytes Á Cardiac muscle contraction Á Calcium transport Á mRNA Á Gene expression
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2002
Slowed relaxation in diabetic cardiomyopathy (CM) is partially related to diminished expression of the sarcoplasmic reticulum (SR) Ca2+-ATPase SERCA2a. To evaluate the impact of SERCA2a overexpression on SR Ca2+ handling in diabetic CM, we 1) generated transgenic rats harboring a human cytomegalovirus enhancer/chicken beta-actin promotor-controlled rat SERCA2 transgene (SERCA2-TGR), 2) characterized their SR phenotype, and 3) examined whether transgene expression may rescue SR Ca2+ transport in streptozotocin-induced diabetes. The transgene was expressed in all heart chambers. Compared to wild-type (WT) rats, a heterozygous line exhibited increased SERCA2 mRNA (1.5-fold), SERCA2 protein (+26%) and SR Ca2+ uptake (+37%). Phospholamban expression was not altered. In SERCA2-TGR, contraction amplitude (+48%) and rates of contraction (+34%) and relaxation (+35%) of isolated papillary muscles (PM) were increased (P2+ uptake and SERCA2 protein of SERCA2-TGR were 1.3-fold higher (P2+ uptake...
Heart Rhythm, 2018
Background: Type-2 diabetes (T2D) increases the arrhythmias risk through incompletely elucidated mechanisms. Ventricular arrhythmias could be initiated by delayed afterdepolarizations (DADs) resulting from elevated spontaneous sarcoplasmic reticulum (SR) Ca 2+ release (SR Ca 2+ leak). Objective: To test the role of DADs and SR Ca 2+ leak in triggering arrhythmias in T2D hearts. Methods: We compared rats with late-onset T2D that display pancreatic and cardiac phenotypes similar to those in humans with T2D (HIP rats) and their non-diabetic littermates (WT). Results: HIP rats showed higher propensity for premature ventricular complexes and ventricular tachyarrhythmias while HIP myocytes displayed more frequent DADs and had lower SR Ca 2+ content compared to the WT. However, the threshold SR Ca 2+ at which depolarizing transient inward currents (I ti s) are generated was also significantly decreased in HIP myocytes and was below the actual SR Ca 2+ load, which explains the increased DAD incidence despite reduced Ca 2+ in SR. In agreement with these findings, Ca 2+ spark frequency was augmented in myocytes from HIP vs. WT rats, which suggests activation of ryanodine receptors (RyR) in HIP hearts. Indeed, RyR phosphorylation (by CaMKII and PKA) and oxidation are enhanced in HIP hearts, while there is no RyR O-GlcNAcylation in either HIP or control hearts. CaMKII inhibition dissipated the difference in Ca 2+ spark frequency between HIP and WT myocytes. Conclusions: The threshold SR Ca 2+ for generating depolarizing I ti s is lower in T2D due to RyR activation following hyperphosphorylation and oxidation, which favors the occurrence of DADs despite low SR Ca 2+ loads.
Scientific Reports
Systolic and diastolic dysfunction in diabetes have frequently been associated with abnormal calcium (Ca2+) regulation. However, there is emerging evidence that Ca2+ mishandling alone is insufficient to fully explain diabetic heart dysfunction, with focus shifting to the properties of the myofilament proteins. Our aim was to examine the effects of diabetes on myofilament Ca2+ sensitivity and Ca2+ handling in left ventricular tissues isolated from the same type 2 diabetic rat hearts. We measured the force-pCa relationship in skinned left ventricular cardiomyocytes isolated from 20-week-old type 2 diabetic and non-diabetic rats. Myofilament Ca2+ sensitivity was greater in the diabetic relative to non-diabetic cardiomyocytes, and this corresponded with lower phosphorylation of cardiac troponin I (cTnI) at ser23/24 in the diabetic left ventricular tissues. Protein expression of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), phosphorylation of phospholamban (PLB) at Ser16, and SERCA/PL...
Calcium signaling in diabetic cardiomyocytes
Cell Calcium, 2014
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 Ca 2+ 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 Ca 2+ fluxes alteration reported on diabetes, and provide some new data on differential modulation of Ca 2+ 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.