Hypertrophied myocardium is vulnerable to ischemia reperfusion injury and refractory to rapamycin-induced protection due to increased oxidative/nitrative stress

Left ventricular hypertrophy (LVH) is causally related to increased morbidity and mortality fol- lowing acutemyocardial infarction (AMI) via still unknownmechanisms. Although rapamycin exerts cardioprotective effects against myocardial ischemia/reperfusion (MI/R) injury in nor- mal animals, whether rapamycin-elicited cardioprotection is altered in the presence of LVH has yet to be determined. Pressure overload induced cardiac hypertrophied mice and sham-operated controls were exposed to AMI by coronary artery ligation, and treated with vehicle or rapamycin 10 min before reperfusion. Rapamycin produced marked cardiopro- tection in normal control mice, whereas pressure overload induced cardiac hypertrophied mice manifested enhanced myocardial injury, and was refractory to rapamycin-elicited car- dioprotection evidenced by augmented infarct size, aggravated cardiomyocyte apopto- sis, and worsening cardiac function. Rapamycin alleviated MI/R injury via ERK-dependent antioxidative pathways in normal mice, whereas cardiac hypertrophied mice manifested markedly exacerbated oxidative/nitrative stress after MI/R evidenced by the increased iNOS/gp91phox expression, superoxide production, total NO metabolites, and nitrotyrosine content. Moreover, scavenging superoxide or peroxynitrite by selective gp91phox assem- bly inhibitor gp91ds-tat or ONOO− scavenger EUK134 markedly ameliorated MI/R injury, as shown by reduced myocardial oxidative/nitrative stress, alleviated myocardial infarc- tion, hindered cardiomyocyte apoptosis, and improved cardiac function in aortic-banded mice. However, no additional cardioprotective effects were achieved when we combined rapamycin and gp91ds-tat or EUK134 in ischemic/reperfused hearts with or without LVH. These results suggest that cardiac hypertrophy attenuated rapamycin-induced cardiopro- tection by increasing oxidative/nitrative stress and scavenging superoxide/peroxynitrite pro- tects the hypertrophied heart from MI/R. In