Abstract
BackgroundNumerous evidences suggest that diabetic heart is characterized by compromised ventricular contraction and prolonged relaxation attributable to multiple causative factors including calcium accumulation, oxidative stress and apoptosis. Therapeutic interventions to prevent calcium accumulation and oxidative stress could be therefore helpful in improving the cardiac function under diabetic condition.MethodsThis study was designed to examine the effect of long-acting calcium channel blocker (CCB), Azelnidipine (AZL) on contractile dysfunction, intracellular calcium (Ca2+) cycling proteins, stress-activated signaling molecules and apoptosis on cardiomyocytes in diabetes. Adult male Wistar rats were made diabetic by a single intraperitoneal (IP) injection of streptozotocin (STZ). Contractile functions were traced from live diabetic rats to isolated individual cardiomyocytes including peak shortening (PS), time-to-PS (TPS), time-to-relengthening (TR90), maximal velocity of shortening/relengthening (± dL/dt) and intracellular Ca2+ fluorescence.ResultsDiabetic heart showed significantly depressed PS, ± dL/dt, prolonged TPS, TR90 and intracellular Ca2+ clearing and showed an elevated resting intracellular Ca2+. AZL itself exhibited little effect on myocyte mechanics but it significantly alleviated STZ-induced myocyte contractile dysfunction. Diabetes increased the levels of superoxide, enhanced expression of the cardiac damage markers like troponin I, p67phox NADPH oxidase subunit, restored the levels of the mitochondrial superoxide dismutase (Mn-SOD), calcium regulatory proteins RyR2 and SERCA2a, and suppressed the levels of the anti-apoptotic Bcl-2 protein. All of these STZ-induced alterations were reconciled by AZL treatment.ConclusionCollectively, the data suggest beneficial effect of AZL in diabetic cardiomyopathy via altering intracellular Ca2+ handling proteins and preventing apoptosis by its antioxidant property.
Highlights
Numerous evidences suggest that diabetic heart is characterized by compromised ventricular contraction and prolonged relaxation attributable to multiple causative factors including calcium accumulation, oxidative stress and apoptosis
AZL neutralizes the increased expression levels of contractile proteins (Troponin I) in diabetic heart Since mechanical dysfunction that characterizes diabetic cardiomyopathy plays an essential role in the Ca2+ regulation of muscle contraction, we studied the effect of AZL on the expression level of cardiac Troponin I in our experimental model
The key findings of our present study demonstrated that AZL treatment for 12 weeks in diabetic animal inhibits the development of early characteristics of diabetic cardiomyopathy, such as, prolonged relaxation and abnormal E-C coupling in vivo in the intact myocardium as well as in the isolated ventricular myocytes
Summary
Numerous evidences suggest that diabetic heart is characterized by compromised ventricular contraction and prolonged relaxation attributable to multiple causative factors including calcium accumulation, oxidative stress and apoptosis. Individuals with diabetes develop cardiomyopathy independent of coronary artery disease, hypertension or atherosclerosis [1,2,3]. This ‘diabetic cardiomyopathy’ is characterized in the early stages by reduced relaxation rates (diastolic dysfunction) while in later stages the systolic dysfunction becomes more prominent [4,5,6]. Higher myocardial NADPH oxidase activity and increased mitochondrial ROS generation have been detected in diabetes way before diastolic dysfunction is detected indicating a subtle role of hyperglycemia in generation of ROS [21,22,23,24]. Improving the abnormal Ca2+ flux in the heart with calcium channel blockers (CCBs) that possesses additional antioxidant property is an attractive strategy to effectively normalize the disturbed Ca2+ transients and improve contractile function
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