Impact of diabetes on cardiomyocyte apoptosis and connexin43 gap junction integrity: role of pharmacological modulation.
The integrity of myocardial structures plays a crucial role in signal transductions and cardiac function. The aim of this study was to test the hypothesis that diabetes mellitus (DM) exerts adverse effects on the integrity of gap junctions (GJs) and induces cellular apoptosis in rat cardiomyocytes that can be abolished by simvastatin or losartan therapy. An experimental model of DM (induced by streptozocin 60 mg/kg body weight) in adult male rats (n = 24) was utilized to investigate the integrity of GJs containing connexin43 (Cx43) and the incidence of cellular apoptosis in the left ventricular myocardium. These rats were divided into 3 groups; group I (insulin therapy only), group II (insulin plus simvastatin 20 mg/kg/day), and group III (insulin plus losartan 20 mg/kg/day). Diabetic rats and 8 healthy rats (group IV) were sacrificed at 3 weeks following DM induction for immunofluorescence analysis. The experimental results demonstrated that the number of intact Cx43 GJs and the integrated area (mum(2)) constituted by clusters of Cx43 spots were significantly higher in groups II and IV than in group III, and in groups II-IV than in group I (all P values < 0.05). Additionally, the number of apoptotic bodies was remarkably higher in group I than in groups II-IV, and notably higher in groups II-III than in group IV (all P values < 0.05). Simvastatin is more effective than losartan at inhibiting the effects of DM on the integrity of myocardial ultrastructures. Both drugs effectively prevent cellular apoptosis in diabetic rat heart.
Sheu
Jiunn-Jye
JJ
Department of Cardiovascular Surgery, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung Hsien, Taiwan, ROC.
Chang
Li-Teh
LT
Chiang
Chiang-Hua
CH
Sun
Cheuk-Kwan
CK
Chang
Nyuk-Kong
NK
Youssef
Ali A
AA
Wu
Chiung-Jen
CJ
Lee
Fan-Yen
FY
Yip
Hon-Kan
HK
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D018031:Connexin 43 / Q000187:drug effects* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D017629:Gap Junctions / Q000187:drug effects* / Q000502:physiology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D007328:Insulin / Q000008:administration & dosage; D019808:Losartan / Q000494:pharmacology; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000494:pharmacology
D047228:Angiotensin II Type 1 Receptor Blockers; D018031:Connexin 43; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D019821:Simvastatin; D019808:Losartan