Anti-apoptotic effects of rosiglitazone in hypercholesterolemic rabbits subjected to myocardial ischemia and reperfusion

objectives: This study examined the effects of diet-induced hypercholesterolemia on the extent of postischemic myocyte apoptosis and elucidated the potential mechanisms involved. Furthermore, the effects of rosiglitazone (RSG) on postischemic myocardial apoptosis in HC rabbits were investigated. Methods: Male New Zealand rabbits were fed normal or high cholesterol diets for 8 weeks. Three weeks after being fed a high cholesterol diet, HC rabbits were randomized to receive vehicle or RSG during the remaining 5 weeks. Rabbits were then subjected to 60 min of coronary Occlusion followed by 4 h of reperfusion. Results: Compared with rabbits fed. with a normal diet, HC rabbits had increased caspase-3 activity, apoptotic cell death and retarded contractile function recovery after reperfusion. HC increased iNOS expression, total NOx and nitrotyrosine contents, indicating that an increased nitrative stress occurred in HC myocardial tissue. Activity of a hypertrophic/anti-apoptotic mitogen-activated protein kinase (MAPK), ERK1/2, was significantly decreased while activation of a pro, apoptotic MAPK, p38, was increased. Treatment with RSG in HC rabbits attenuated postischemic myocardial nitrative stress, restored a beneficial balance between pro- and anti-apoptotic MAPK signaling, reduced postischemic myocardial apoptosis, and improved cardiac functional recovery. Conclusions: Our results demonstrated that HC increased postischemic myocardial apoptosis likely by increasing the production of pro-apoptotic molecules, activating pro-apoptotic signaling pathways and inhibiting anti-apoptotic signaling. In addition, our results suggest that peroxisome proliferator-activated receptor (PPAR) gamma agonists may not only attenuate the formation of atherosclerosis associated with hypercholesterolemia as previously reported, but may also protect the heart from subsequent ischemic/reperfusion-induced myocardial apoptosis. (C) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.