Targeting apoptosis in the heart of streptozotocin-induced diabetic rats

ABSTRACT

To address the issue of cardiomyocyte apoptosis as a possible cause of diabetic cardiomyopathy and whether it would be possible to suppress this apoptosis by the use of PPAR gamma agonists [glitazones] and PPAR alpha agonists [fibrates], versus insulin. forty male rats were made diabetic by intraperitoneal [i.p.] streptozotocin [STZ] injection and were divided into four groups group II [STZ-injected rats], groups III, IV and V [STZ-injected rats treated with insulin, PPAR gamma agonist [rosiglitazone] and PPAR alpha agonist [bezafirate] respectively, for twelve weeks starting one week following STZ injection]. Additionally, ten rats were injected i.p. by a single dose of saline and served as a control for group II. At the end of the experimental period, plasma glucose was measured. Left ventricular [LV] papillary muscles isometric force [developed tension [DT]] was determined. Oxidative stress as assessed by cardiac malondialdehyde [MDA] and reduced glutathione [GSH] concentrations as well as caspase-3 activity as an index of apoptosis were determined. STZ-injection induced diabetes, evidenced by significant higher mean value in plasma glucose concentration in group II compared to that of the control group I. Significant cardiomyopathy could be observed, in the form of significantly decreased DT of LV papillary muscles in group II compared to the control group I. STZ-injection resulted in oxidative stress evidenced by significant higher mean value in cardiac MDA concentration and significant lower mean value in cardiac GSH concentration in group II compared to the control group I. STZ-injection resulted in cardiac apoptosis evidenced by significant higher mean value in cardiac caspase-3 activity in group II compared to the control group I. The use of insulin, rosiglitazone as well as bezafibrate caused a significant decrease in plasma glucose concentration as well as a significant increase in body weight compared to group II. The use of insulin as well as rosiglitazone, but not bezafibrate, decreased cardiac caspase-3 activity and improved oxidative stress parameters evidenced by significant lower mean value in cardiac MDA concentration and significant higher mean value in cardiac GSH concentration compared to group II. Rosigitazone but neither insulin nor bezafibrate resulted in significant improvement of LV papillary muscle DT compared to group II. The results of the present study support the hypothesis that apoptosis plays a key role in the pathophysiology of diabetic cardiomyopathy and demonstrate that the use of PPAR gamma agonists might have a protective role against diabetic cardiomyopathy. We recommend further human studies to evaluate the role of the addition of PPAR gamma agonists to the treatment regimen of diabetes, from the onset of the disease, in protection against diabetic cardiomyopathy. Although the use of PPAR-alpha agonists seems counterintuitive in light of the current findings, the benefit of reduced delivery of fatty acids to the myocardium may outweigh the effects of activating the cardiac PPARalpha pathway in the diabetic patient