Hyperglycemia-Induced Apoptosis in Mouse Myocardium

Abstract

Diabetic cardiomyopathy is related directly to hyperglycemia. Cell death such as apoptosis plays a critical role in cardiac pathogenesis. Whether hyperglycemia induces myocardial apoptosis, leading to diabetic cardiomyopathy, remains unclear. We tested the hypothesis that apoptotic cell death occurs in the diabetic myocardium through mitochondrial cytochrome c-mediated caspase-3 activation pathway. Diabetic mice produced by streptozotocin and H9c2 cardiac myoblast cells exposed to high levels of glucose were used. In the hearts of diabetic mice, apoptotic cell death occurred as detected by terminal deoxynucleotidyl transferasemediated dUTP nick-end labeling (TUNEL) assay. Correspondingly, caspase-3 activation as determined by enzymatic assay and mitochondrial cytochrome c release detected by Western blotting analysis were observed. Supplementation of insulin inhibited diabetesinduced myocardial apoptosis as well as suppressed hyperglycemia. To explore whether apoptosis in diabetic hearts is related directly to hyperglycemia, we exposed cardiac myoblast H9c2 cells to high levels of glucose (22 and 33 mmol/l) in cultures. Apoptotic cell death was detected by TUNEL assay and DAPI nuclear staining. Caspase-3 activation with a concomitant mitochondrial cytochrome c release was also observed. Apoptosis or activation of caspase-3 was not observed in the cultures exposed to the same concentrations of mannitol. Inhibition of caspase-3 with a specific inhibitor, Ac-DEVD-cmk, suppressed apoptosis induced by high levels of glucose. In addition, reactive oxygen species (ROS) generation was detected in the cells exposed to high levels of glucose. These results suggest that hyperglycemia directly induces apoptotic cell death in the myocardium in vivo. Hyperglycemiainduced myocardial apoptosis is mediated, at least in part, by activation of the cytochrome c-activated caspase-3 pathway, which may be triggered by ROS derived from high levels of glucose.

ACE-inhibition is superior to endothelin A receptor blockade in preventing abnormal capillary supply and fibrosis of the heart in experimental diabetes

“…One explanation proposed by some authors is that damaged cardiomyocytes are unable to synthesise ET-1 in response to Ang II stimulation [13,39,46]. For diabetes this explanation is excluded by our results.…”

“…The maximal decrease in bp was seen with combination treatment. The increase in systolic bp in diabetes mellitus could be related to the stimulatory effect of hyperglycaemia on the RAS [36,37,38] or generation of oxygen radical species reducing the availability of nitric oxide [39]. A normalisation of systemic bp in nonselective ET-1 blockade in diabetic rats is described [40].…”

“…This hypothesis could explain the superior efficacy of the ACE-i in our study. Interestingly, in diabetes apoptosis of cardiomyocytes seem to occur independent of hypertension [39].…”

Determinants of subclinical diabetic heart disease

“…However, it may also be structural-both apoptosis and necrosis have been identified in diabetic heart disease and myocyte cell death caused by either apoptosis or necrosis or both may be a major reason for the reduced myocardial contractility. Evidence in vivo has shown that hyperglycaemia directly induces apoptotic cell death and myocyte necrosis in the myocardium, triggered by reactive oxygen species derived from high levels of glucose [15]. Myocyte apoptosis and necrosis initiated by hyperglycaemia result in myocardial cell loss, which may impair the ability of the myocardium to develop force, accounting for reduced contractility.…”

Sustained cardiomyocyte apoptosis and left ventricular remodelling after myocardial infarction in experimental diabetes

“…As recent studies have shown that diabetes could be associated with enhanced susceptibility to apoptosis [5], we wanted to study in an experimental rat MI model, whether cardiomyocyte apoptosis is increased in diaDiabetic patients have about a two-fold increase in a risk of short-and long-term mortality after myocardial infarction (MI). Even after adjustment for the infarct betic compared to non-diabetic animals after MI, and whether it would relate to cardiac remodelling.…”