AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury

Russell, Raymond R.; Li, Ji; Coven, David L.; Pypaert, Marc; Zechner, Christoph Peter Gerhard; Palmeri, Monica; Giordano, Frank J.; Mu, James; Birnbaum, Morris J.; Young, Lawrence H.

doi:10.1172/jci19297

Cited by 648 publications

(476 citation statements)

References 69 publications

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“…There is evidence indicating that ischemia-induced AMPK activation exerts a protective effect on the heart (Russell et al 2004, Calvert et al 2008. Testosterone induced further AMPK activation and upregulated PGC1A compared with testosterone deprivation, indicating that testosterone replacement protected mitochondrial and cardiac function.…”

Section: Discussionmentioning

confidence: 97%

Testosterone replacement attenuates mitochondrial damage in a rat model of myocardial infarction

Wang¹,

Yang²,

Sun³

et al. 2015

Journal of Endocrinology

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Testosterone can affect cardiovascular disease, but its effects on mitochondrial dynamics in the post-infarct myocardium remain unclear. To observe the effects of testosterone replacement, a rat model of castration-myocardial infarction (MI) was established by ligating the left anterior descending coronary artery 2 weeks after castration with or without testosterone treatment. Expression of mitochondrial fission and fusion proteins was detected by western blot and immunofluorescence 14 days after MI. Cardiac function, myocardial inflammatory infiltration and fibrosis, cardiomyocyte apoptosis, mitochondrial microstructure, and ATP levels were also assessed. Compared with MI rats, castrated rats showed aggravated mitochondrial and myocardial insults, including mitochondrial swelling and disordered arrangement; loss of cristae, reduced mitochondrial length; decreased ATP levels; cardiomyocyte apoptosis; and impaired cardiac function. Results of western blotting analyses indicated that castration downregulated peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1A) and mitofusin 2, but upregulated dynamin-related protein 1. The results were also supported by results obtained using immunofluorescence. However, these detrimental effects were reversed by testosterone supplementation, which also elevated the upstream AMP-activated protein kinase (AMPK) activation of PGC1A. Thus, testosterone can protect mitochondria in the post-infarct myocardium, partly via the AMPK-PGC1A pathway, thereby decreasing mitochondrial dysfunction and cardiomyocyte apoptosis. The effects of testosterone were confirmed by the results of ELISA analyses.

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Section: Discussionmentioning

confidence: 97%

Testosterone replacement attenuates mitochondrial damage in a rat model of myocardial infarction

Wang¹,

Yang²,

Sun³

et al. 2015

Journal of Endocrinology

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“…Cx43 internalization is an important mechanism during cardiac ischemia [58]. Cardiac ischemia activates Ampkα1 [59], which exerts protective effects in the ischemic heart [60,61]. Similarly, inhibition of Cx43 mitigates cardiac ischemia reperfusion injury [62].…”

Section: Discussionmentioning

confidence: 99%

AMP-Activated Protein Kinase α1 Regulates Cardiac Gap Junction Protein Connexin 43 and Electrical Remodeling Following Pressure Overload

Alesutan

Voelkl²,

Stöckigt³

et al. 2015

Cell Physiol Biochem

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Background/Aims: Adenosine 5'-monophosphate (AMP)-activated protein kinase (Ampk) modulates a wide array of cellular functions and regulates various ion channels and transporters. In failing human hearts an increased Ampkα1 activity was observed. The present study aimed to uncover the impact of Ampkα1 on cardiac electrical remodeling. Methods: Gene-targeted mice lacking functional Ampkα1 (Ampkα1-/-) and corresponding wild-type mice were exposed to pressure overload by “transverse aortic constriction” (TAC). In vivo electrophysiology was performed with a single catheter technique, myocardial conduction velocities and conduction characteristics investigated in isolated hearts, transcript levels quantified by RT-PCR and protein abundance determined by Western blotting. Moreover, connexin 43 (Cx43) was expressed in Xenopus oocytes with or without coexpression of wild-type or mutant AMPK and Cx43 protein abundance quantified utilizing confocal microscopy. Results: TAC treatment increased Ampkα1 protein expression in cardiac tissue from wild-type mice. TAC further increased left ventricular conduction inhomogeneity and triggered conduction blocks, effects blunted in the Ampkα1^-/- mice. TAC treatment decreased Cx43 protein abundance in cardiac tissue, an effect significantly blunted in the Ampkα1^-/- mice. TAC treatment did not modify Cx43 mRNA levels but increased ubiquitination of Cx43 protein, an effect mitigated by Ampkα1 deficiency. As shown in Xenopus oocytes, Cx43 cell membrane protein abundance was significantly downregulated by wild-type AMPK^WT and constitutively active AMPK^γR70Q, but not by catalytically inactive AMPK^αK45R. Conclusion: Ampkα1 stimulates ubiquitination of the gap junction protein Cx43, thereby contributing to gap junction remodeling following pressure overload.

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“…Because Akt and AMP-activated protein kinase are important regulators that protect cardiomyocytes from apoptosis, [13][14][15][16] we evaluated phosphorylation levels of Akt and AMP-activated protein kinase in NRVMs by Western blot analysis. Treatment of NRVMs with NDNF protein increased phosphorylation of Akt at Ser-473 in a time-dependent manner, whereas NDNF had no effects on phosphorylation of AMP-activated protein kinase at Thr-172 ( Figure 4A).…”

Section: Ndnf Reduces Cardiomyocyte Apoptosis Through Focal Adhesion mentioning

confidence: 99%

Neuron-Derived Neurotrophic Factor Ameliorates Adverse Cardiac Remodeling After Experimental Myocardial Infarction

Joki

Ohashi

Yuasa

et al. 2015

Circ: Heart Failure

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Background— Myocardial infarction (MI) is one of the major causes of death worldwide. Chronic heart failure is a serious complication of MI that leads to poor prognosis. We recently found that neuron-derived neurotrophic factor (NDNF) is a proangiogenic secretory protein that is upregulated in ischemic skeletal muscle. Here, we examined whether NDNF modulates cardiac remodeling in response to chronic ischemia. Methods and Results— C57BL/6J wild-type mice were subjected to the permanent ligation of the left anterior descending coronary artery to create MI. Adenoviral vectors expressing NDNF or β-galactosidase (control) were intramuscularly injected into mice 3 days before permanent left anterior descending coronary artery ligation. Intramuscular administration of adenoviral vectors expressing NDNF to mice resulted in increased levels of circulating NDNF. Adenoviral vectors expressing NDNF administration improved left ventricular systolic dysfunction and dilatation after MI surgery. Moreover, adenoviral vectors expressing NDNF enhanced capillary formation and reduced cardiomyocyte apoptosis and hypertrophy in the post-MI hearts. Treatment of cultured cardiomyocytes with recombinant NDNF protein led to reduced apoptosis under conditions of hypoxia. NDNF also promoted the phosphorylation of Akt and focal adhesion kinase in cardiomyocytes. Blockade of focal adhesion kinase activation blocked the stimulatory effects of NDNF on cardiomyocyte survival and Akt phosphorylation. Similarly, treatment of cultured endothelial cells with NDNF protein led to enhancement of network formation and Akt phosphorylation, which was diminished by focal adhesion kinase inhibition. Conclusions— These data suggest that NDNF ameliorates adverse myocardial remodeling after MI by its abilities to enhance myocyte survival and angiogenesis in the heart through focal adhesion kinase/Akt-dependent mechanisms.

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AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury

Cited by 648 publications

References 69 publications

Testosterone replacement attenuates mitochondrial damage in a rat model of myocardial infarction

Testosterone replacement attenuates mitochondrial damage in a rat model of myocardial infarction

AMP-Activated Protein Kinase α1 Regulates Cardiac Gap Junction Protein Connexin 43 and Electrical Remodeling Following Pressure Overload

Neuron-Derived Neurotrophic Factor Ameliorates Adverse Cardiac Remodeling After Experimental Myocardial Infarction

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