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Activated protein C protects against pressure overload-induced hypertrophy through AMPK signaling

Published on Jan 1, 2018in Biochemical and Biophysical Research Communications2.71
· DOI :10.1016/j.bbrc.2017.12.125
Courtney Cates9
Estimated H-index: 9
(UMMC: University of Mississippi Medical Center),
Thomas Rousselle5
Estimated H-index: 5
(UMMC: University of Mississippi Medical Center)
+ 6 AuthorsJi Li6
Estimated H-index: 6
(UMMC: University of Mississippi Medical Center)
Abstract
Abstract We found that the anticoagulant plasma protease, activated protein C (APC), stimulates the energy sensor kinase, AMPK, in the stressed heart by activating protease-activated receptor 1 (PAR1) on cardiomyocytes. Wild-type (WT) and AMPK-kinase dead (KD) transgenic mice were subjected to transverse aortic constriction (TAC) surgery. The results demonstrated that while no phenotypic differences can be observed between WT and AMPK-KD mice under normal physiological conditions, AMPK-KD mice exhibit significantly larger hearts after 4 weeks of TAC surgery. Analysis by echocardiography suggested that the impairment in the cardiac function of AMPK-KD hearts is significantly greater than that of WT hearts. Immunohistochemical staining revealed increased macrophage infiltration and ROS generation in AMPK-KD hearts after 4 weeks of TAC surgery. Immunoblotting results demonstrated that the redox markers, pShc 66 , 4-hydroxynonenal and ERK, were all up-regulated at a higher extent in AMPK-KD hearts after 4 weeks of TAC surgery. Administration of APC-WT and the signaling selective APC-2Cys mutant, but not the anticoagulant selective APC-E170A mutant, significantly attenuated pressure overload-induced hypertrophy and fibrosis. Macrophage infiltration and pShc 66 activation caused by pressure overload were also inhibited by APC and APC-2Cys but not by APC-E170A. Therefore, the cardiac AMPK protects against pressure overload-induced hypertrophy and the signaling selective APC-2Cys may have therapeutic potential for treating hypertension-related hypertrophy without increasing the risk of bleeding.
  • References (38)
  • Citations (2)
References38
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#1Miranda M. Sung (U of A: University of Alberta)H-Index: 11
#2Beshay N.M. Zordoky (U of A: University of Alberta)H-Index: 21
Last.Bruce E. Kemp (St. Vincent's Institute of Medical Research)H-Index: 95
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#1Yina Ma (UB: University at Buffalo)H-Index: 1
#2Ji Li (UB: University at Buffalo)H-Index: 1
#1Alex Morrison (UB: University at Buffalo)H-Index: 8
#2Li Chen (JLU: Jilin University)H-Index: 1
Last.Ji Li (UB: University at Buffalo)H-Index: 11
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#1Xin Xu (UMN: University of Minnesota)H-Index: 30
#2Zhongbing Lu (CAS: Chinese Academy of Sciences)H-Index: 21
Last.Yi Tao (UMN: University of Minnesota)H-Index: 7
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