Cardioprotective effects of rosiglitazone are associated with selective overexpression of type 2 angiotensin receptors and inhibition of p42/44 MAPK.
Current evidence points to renin-angiotensin system as a key mediator in ischemia-reperfusion injury. Rosiglitazone, a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligand, has recently been shown to confer cardioprotection against ischemia-reperfusion in animal models. We sought to examine the expression of ANG II receptors during PPAR-gamma-mediated cardioprotection. Male Sprague-Dawley rats (nondiabetic) were fed either regular rat chow (control diet group, n = 9) or rosiglitazone-rich diet (rosiglitazone-rich diet group, n = 9) and were subjected to 1 h of myocardial ischemia followed by 1 h of reperfusion. A third group of rats had only thoracotomy and pericardiotomy and served as a sham control group (n = 9). Hemodynamics, infarct size, and expression of ANG II type 1 and type 2 receptors (AT1 and AT2) were measured in all groups. There was a 58% reduction of infarct size in the rosiglitazone-rich diet group (P < 0.01 vs. control diet group). Increased myocardial expression of AT(1) receptors in the ischemic-reperfused myocardium was attenuated in the rosiglitazone-rich diet group (P < 0.05 vs. control diet group). Importantly, myocardial AT2 mRNA and protein expression were significantly increased (by >100-fold) in the rosiglitazone-rich diet group (P < 0.05). These changes were accompanied by inhibition of p42/44 MAPK in the rosiglitazone-rich diet group, while the Akt1 expression, believed to mediate insulin sensitization, remained similar in all three groups. The cardioprotective effects of rosiglitazone against myocardial ischemia-reperfusion injury are independent of its insulin-sensitizing properties and are associated with significant overexpression of AT2 receptors along with inhibition of p42/44 MAPK.
Dept. of Internal Medicine, Div. of Cardiovascular Medicine, Univ. of Arkansas for Medical Sciences, 4301 W. Markham St., #532, Little Rock, AR 72205, USA. molavibehzad@uams.edu
Behzad
B
Molavi
Jiawei
J
Chen
J L
JL
Mehta
D000803:Angiotensin I / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D006439:Hemodynamics / Q000502:physiology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007150:Immunohistochemistry; D008024:Ligands; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors*; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D047495:PPAR gamma / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044139:Receptor, Angiotensin, Type 2 / Q000096:biosynthesis*; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
D001786:Blood Glucose; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D008024:Ligands; D047495:PPAR gamma; D044139:Receptor, Angiotensin, Type 2; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000804:Angiotensin II; D000803:Angiotensin I; C494920:Akt1 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1