Modulation of PPAR-gamma by telmisartan protects the heart against myocardial infarction in experimental diabetes.

Abstract

Telmisartan, an angiotensin II-receptor blocker (ARB), is a partial agonist of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). We investigated whether telmisartan improved the pathophysiology of myocardial infarction in diabetes partially through the PPAR-gamma pathway by assessing a variety of indices, e.g., hemodynamic, biochemical, histoarchitectural changes, and apoptosis. Diabetes was induced by a single dose of streptozotocin (70 mg/kg, IP). Diabetic rats received either telmisartan (10 mg/kg/day, orally), the PPAR-gamma antagonist GW9662 (1 mg/kg/day, IP), or both for 14 days with concurrent administration of isoproterenol (85 mg/kg, SC) on days 13 and 14. Compared with diabetic controls, diabetic rats with myocardial infarction exhibited altered hemodynamic profiles and reduction in the activities of creatine kinase-MB isoenzyme, lactate dehydrogenase, superoxide dismutase, catalase, and glutathione level along with increased level of malondialdehyde in the heart. Further, diabetic animals with myocardial infarction exhibited increased myonecrosis, edema, and apoptotic cell death. Treatment with telmisartan significantly improved the redox status of the myocardium with subsequent cardiac functional recovery. However, significant effects were lowered in animals treated with telmisartan plus GW9662. Telmisartan markedly inhibited Bax expression, TUNEL-positive cells, myonecrosis, and edema. On the other hand, administration of telmisartan plus GW9662 did not elicit the same effects, nor did they increase Bcl-2 protein expression in isoproterenol-induced myocardially infarcted diabetic rats when administered concomitantly or individually. Moreover, down-regulated PPAR-gamma expression in myocardially infarcted diabetic hearts was increased by telmisartan treatment. In addition to class effects of ARBs, telmisartan reduces oxidative stress and apoptosis and improves cardiac function via the PPAR-gamma pathway.

• Authors: Sameer Goyal, Sachin Arora, Tarun Kumar Bhatt, Prasenjit Das, Amit Sharma, Santosh Kumari, Dharamvir Singh Arya
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 185 Issue 3 Pg. 271-80 (May 14 2010) ISSN: 1872-7786 [Electronic] Ireland
• PMID: 20307515 (Publication Type: Journal Article)
• Copyright: Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Benzimidazoles
• Benzoates
• Cardiotonic Agents
• PPAR gamma
• Telmisartan

Topics

• Animals
• Benzimidazoles (pharmacology, therapeutic use)
• Benzoates (pharmacology, therapeutic use)
• Cardiotonic Agents (pharmacology, therapeutic use)
• Diabetes Mellitus, Experimental (drug therapy, metabolism)
• Disease Models, Animal
• Heart (drug effects)
• Male
• Myocardial Infarction (drug therapy, metabolism)
• Myocardium (metabolism)
• PPAR gamma (metabolism)
• Rats
• Rats, Wistar
• Telmisartan