Abstract 11919: 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. 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, it 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 occluded and subsequently released, and a mouse model of transverse aortic constriction (TAC), in which pressure overload hypertrophy was induced in 4 weeks. Results: JNK-IN-8 treatment significantly reduced myocardial infarct area by 40% in mouse ischemia and reperfusion (I/R) model as compared to the vehicle groups (p<0.01). Interestingly, the immunohistochemistry data showed that JNK-IN-8 treatment attenuated the macrophage infiltration and caspase-3 executed apoptosis signaling in TAC-induced heart failure mice (p<0.01 vs. vehicle groups). Moreover, the staining of wheat germ agglutinin (WGA) and Masson trichrome staining revealed that there are significant decreases in hypertrophy and fibrosis in the hearts of JNK-IN-8 treated TAC-induced heart failure mice. Furthermore, the immunoblotting data demonstrated that JNK-IN-8 treatment selectively attenuated both I/R- and pressure overload-induced JNK and downstream oxidative stress p-SHC (p66), inflammatory NF-kappaB signaling pathways, while the levels of other mitogen protein kinase family signals (p-p38 and p-ERK) remained unchanged, indicating the specificity of JNK-IN-8 on JNK signaling in the heart. Conclusions: JNK-IN-8 reduces myocardial infarction caused by ischemia and reperfusion, and attenuates pressure overload-induced inflammation, apoptosis, hypertrophy and fibrosis. Thus JNK-IN-8 is a potential therapeutic drug for I/R- and pressure overload-induced heart failure.