Abstract 025: AMP-activated Protein Kinase Mediates Pressure Overload-induced Hypertrophy

Abstract

Hypertension is a major risk factor of death and disability from heart and vascular diseases. Heart hypertrophy caused by pressure overload is characterized by the activation of adenosine monophosphate-activated protein kinase (AMPK), which is the major energy sensor in the heart. However, the anti-inflammatory effect of AMPK has not been investigated in the hypertrophy model. Activated protein C (APC) is a vitamin-K dependent plasma serine protease which inhibits blood clotting, and APC is an endogenous AMPK agonist. This study was designed to examine the role of AMPK in hypertrophy and the underlying mechanisms by which APC inhibits heart hypotrophy by pressure overload. We hypothesize that AMPK play a role in preventing heart from hypertrophy induced by pressure overload. APC could inhibit high blood pressure-induced hypertrophy via activation of AMPK signaling pathway. Wild-type (WT) and AMPK-kinase dead (KD) transgenic mice were subjected to transverse aortic constriction (TAC) surgery. Echocardiography was performed to evaluate the heart function, and histology staining revealed the morphological changes. Real-time PCR and western blotting were used to detect the signaling changes of both mRNA and protein expression levels. There is no phenotype difference between WT and AMPK-KD mice under normal physiological conditions. However after 4 weeks of TAC surgery, AMPK-KD mice demonstrated significantly bigger heart than WT mice (p<0.05), and the cardiac functions measured by echocardiography in AMPK-KD hearts were significantly impaired as compared with WT hearts (p<0.05). The immunohistochemical staining showed that the increased macrophage infiltration and reactive oxygen species (ROS) including activated p66shc, 4-HNE and ERK were observed in the AMPK-KD hearts after 4 weeks of TAC surgery (all p<0.05 versus WT hearts). APC administration significantly attenuated hypertrophy and fibrosis caused by pressure overload, and macrophage infiltration and p66shc activation were also inhibited by APC treatment. Therefore, Cardiac AMPK deficiency aggravates hypertrophy caused by pressure overload. AMPK activator APC could be a therapeutic drug for treatment of hypertrophy by high blood pressure.