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 following acute myocardial infarction (AMI) via still unknown mechanisms. Although rapamycin exerts cardioprotective effects against myocardial ischemia/reperfusion (MI/R) injury in normal animals, whether rapamycin-elicited cardioprotection are 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 cardioprotection in normal control mice, whereas pressure overload-induced cardiac hypertrophied mice manifested enhanced myocardial injury, and was refractory to rapamycin-elicited cardioprotection evidenced by augmented infarct size, aggravated cardiomyocytes apoptosis, 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 assembly inhibitor gp91ds-tat or ONOO- scavenger EUK134 markedly ameliorated MI/R injury, as shown by reduced myocardial oxidative/nitrative stress, alleviated myocardial infarctio...

Source: Clinical Science - November 24, 2017 Category: Biomedical Science Authors: Ma, L.-L., Yin, P.-P., Li, Y., Kong, F.-J., Guo, J.-J., Shi, H.-T., Zhu, J.-B., Zou, Y.-Z., Ge, J.-B. Tags: PublishAheadOfPrint Source Type: research