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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 Communications2.705
· DOI :10.1016/j.bbrc.2017.12.125
Courtney Cates10
Estimated H-index: 10
(UMMC: University of Mississippi Medical Center),
Thomas Rousselle6
Estimated H-index: 6
(UMMC: University of Mississippi Medical Center)
+ 6 AuthorsJi Li34
Estimated H-index: 34
(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, pShc66, 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 pShc66 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)
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References38
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#1Miranda M. Sung (U of A: University of Alberta)H-Index: 12
#2Beshay N.M. Zordoky (U of A: University of Alberta)H-Index: 21
Last. Jason R. B. Dyck (U of A: University of Alberta)H-Index: 58
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AMP-activated protein kinase (AMPK) is thought to be a central player in regulating myocardial metabolism and its activation has been shown to inhibit cardiac hypertrophy. Recently, mice with muscle-specific deletion of AMPK β1/β2 subunits (AMPKβ1β2-deficient mice, β1β2M-KO) have been generated and possess <10% of normal AMPK activity in muscle. However, how/if dramatic AMPK deficiency alters cardiac metabolism, function, or morphology has not been investigated. Therefore, the aim of this study ...
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#1Yina Ma (UB: University at Buffalo)H-Index: 3
#2Ji Li (UB: University at Buffalo)H-Index: 34
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#1Alex Morrison (UB: University at Buffalo)H-Index: 8
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#1Magali BalteauH-Index: 6
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#1Shin Watanabe (Kyoto University)H-Index: 10
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Background The mechanism of cardiac energy production against sustained pressure overload remains to be elucidated. Methods and Results We generated cardiac-specific kinase-dead (kd) calcium/calmodulin-dependent protein kinase kinase-β (CaMKKβ) transgenic (α-MHC CaMKKβkd TG) mice using α-myosin heavy chain (α-MHC) promoter. Although CaMKKβ activity was significantly reduced, these mice had normal cardiac function and morphology at baseline. Here, we show that transverse aortic binding (TAC) in α...
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#1Yina MaH-Index: 2
#2Jinli WangH-Index: 5
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Antithrombin (AT) is a protein of the serpin superfamily involved in regulation of the proteolytic activity of the serine proteases of the coagulation system. AT is known to exhibit anti-inflammatory and cardioprotective properties when it binds to heparan sulfate proteoglycans (HSPGs) on vascular cells. AMP-activated protein kinase (AMPK) plays an important cardioprotective role during myocardial ischaemia and reperfusion (I/R). To determine whether the cardioprotective signaling function of AT...
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#1Katia M.S. GomesH-Index: 6
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Last. Julio Cesar Batista Ferreira (Stanford University)H-Index: 27
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Aims We previously demonstrated that pharmacological activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2) protects the heart against acute ischaemia/reperfusion injury. Here, we determined the benefits of chronic activation of ALDH2 on the progression of heart failure (HF) using a post-myocardial infarction model. Methods and results We showed that a 6-week treatment of myocardial infarction-induced HF rats with a selective ALDH2 activator (Alda-1), starting 4 weeks after myocardial infa...
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#1Xin Xu (UMN: University of Minnesota)H-Index: 30
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Last. Yingjie ChenH-Index: 34
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Activation of AMP-activated protein kinase (AMPK)-α2 protects the heart against pressure overload–induced heart failure in mice. Although metformin is a known activator of AMPK, it is unclear whether its cardioprotection acts independently of an AMPKα2-dependent pathway. Because the role of AMPKα1 stimulation on remodeling of failing hearts is poorly defined, we first studied the effects of disruption of both the AMPKα1 and AMPKα2 genes on the response to transverse aortic constriction–induced l...
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#1Vishal R. Mali (HFHS: Henry Ford Health System)H-Index: 11
#2Suresh S. Palaniyandi (HFHS: Henry Ford Health System)H-Index: 19
Abstract4-hydroxy-2-nonenal (4-HNE), a reactive aldehyde, is generated from polyunsaturated fatty acids (PUFAs) in biological membranes. Reactive oxygen species (ROS) generated during oxidative stress react with PUFAs to form aldehydes like 4-HNE, which inactivates proteins and DNA by forming hybrid covalent chemical addition compounds called adducts. The ensuing chain reaction results in cellular dysfunction and tissue damage. It includes a wide spectrum of events ranging from electron transpor...
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Background: Both chronic hypoxia (CH) and long-term chronic intermittent hypoxia (CIH) exposure lead to right ventricular hypertrophy (RVH). Weight loss is an effective intervention to improve cardiac function and energy metabolism in cardiac hypertrophy. Likewise, caloric restriction (CR) also plays an important role in this cardioprotection through AMPK activation. We aimed to determine the influence of body weight (BW) on RVH, AMPK and related variables by comparing rats exposed to both hypox...
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Activated protein C (APC) is a vitamin-K dependent plasma serine protease, which functions as a natural anticoagulant to downregulate thrombin generation in the clotting cascade. APC also modulates cellular homeostasis by exhibiting potent cytoprotective and anti-inflammatory signaling activities. The beneficial cytoprotective effects of APC have been extensively studied and confirmed in a number of preclinical disease and injury models including sepsis, type-1 diabetes and various ischemia/repe...
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The “Oxygen Paradox” proposes that it is tough for aerobic organisms to live without oxygen, but it is difficult to live with oxygen as well. Assigned a job of incessant pumping, the heart, being an obligate aerobic organ, epitomizes the paradoxical effects of oxygen. Much of them are attributed to the reactive oxygen species (ROS) that mold the embryonic development and normal functioning of the heart under homeostatic conditions on one hand and the progression of cardiovascular diseases on the...
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