Abstract 12019: Inactivation of AMP-activated Protein Kinase Sensitizes Heart to Pressure Overload-induced Hypertrophy
Introduction: Hypertrophy triggers activation of adenosine monophosphate-activated protein kinase (AMPK), an energy sensor in the heart. We have identified activated protein C (APC) is an endogenous AMPK agonist, and the non-anticoagulant APC-2Cys mutant but not the non-signaling APC-E170A mutant stimulates cardiac AMPK activation as well.
Hypothesis: AMPK play a critical role in preventing heart from hypertrophy induced by pressure overload. APC as a AMPK agonist inhibits pressure overload-induced hypertrophy via APC’s cytoprotective signaling activity.
Methods: 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 immunoblotting were used to detect mRNA and protein levels of signaling changes.
Results: There is no phenotype difference between wild type (WT) and AMPK-kinase dead (AMPK KD) mice under normal physiological conditions. However after 4 weeks of TAC surgery, AMPK-KD mice demonstrated significantly bigger heart as compared to WT mice (p<0.05). 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) in AMPK-KD versus WT hearts after 4 weeks of TAC surgery. The immunoblotting results demonstrated that the redox status markers such as p66shc, 4-hydroxynonenal and extracellular signal-regulated kinase (ERK) were up-regulated in the AMPK-KD hearts after 4 weeks of TAC surgery (all p<0.05 versus WT hearts). APC and APC-2Cys but not APC-E170A administration significantly attenuated hypertrophy and fibrosis caused by pressure overload. The macrophage infiltration and p66shc activation caused by pressure overload were also inhibited by APC and APC-2Cys but not by APC-E170A.
Conclusions: Cardiac AMPK inactivation aggravates pressure overload induced hypertrophy. APC-2Cys without anticoagulant activity could be a therapeutic drug for treatment of hypertension-related hypertrophy patients without bleeding risk.
Author Disclosures: J. Wang: None. N. Quan: None. L. Wang: None. X. Chen: None. D. Chu: None. A. Rezaie: None. J. Li: None.
- © 2016 by American Heart Association, Inc.