Abstract 13262: A Potent and Selective Covalent Inhibitor of JNK Protects Heart from both Ischemia/Reperfusion- and Hypertension-induced Heart Failure

Abstract

Introduction: c-Jun NH 2 -terminal kinases (JNKs) are critical mediators of a variety of detrimental stimuli including ischemia-reperfusion (I/R) and mechanical stress induced by pressure overload. Recently, we reported that a novel synthesized highly selective JNK inhibitor, JNK-IN-8, can form an ATP site-directed covalent bond with a conserved cysteine residual in all JNKs. Therefore, JNK-IN-8 may be broadly useful as a pharmacological tool for inhibiting JNK-dependent signal transduction that is involved in various pathological conditions. Hypothesis: The potent JNK inhibitor, JNK-IN-8, could act as a cardioprotectant against ischemia/reperfusion (I/R)- or hypertension-induced heart failure. Methods: The effects of JNK-IN-8 were monitored in a mouse I/R models with the left anterior descending coronary artery (LAD) occluded and subsequently released, and a mouse model of trans-aortic constriction (TAC), in which pressure overload hypertrophy was induced in 2 weeks. Results: JNK-IN-8 significantly reduced myocardial infarct area by 40% in I/R model relative to the vehicle group (p<0.01). Interestingly, the immunohistochemistry data showed that JNK-IN-8 treatment attenuated macrophage infiltration and caspase-3 executed apoptosis in TAC mice (p<0.01 vs. vehicle group). Moreover, the staining of wheat germ agglutinin (WGA) and Masson trichrome revealed a decrease in hypertrophy and fibrosis in the TAC hearts of JNK-IN-8 treated group (p<0.05 vs. vehicle group). The immunoblotting data demonstrated that JNK-IN-8 selectively attenuated both I/R- and pressure overload-induced cardiac JNK and downstream p-p66 shc signaling pathways, while the levels of other family signals (p-p38 and p-ERK) remained unchanged, further indicating the specificity of JNK-IN-8 on JNK signaling in the heart. Conclusions: JNK-IN-8 can reduce I/R-injury induced myocardial infarction size, and attenuate pressure overload induced inflammation, apoptosis, hypertrophy and fibrosis. Thus JNK-IN-8 is a potential therapeutic drug for both I/R injury and pressure overload induced hypertrophy.