The beneficial effects of AMP kinase activation against oxidative stress are associated with prevention of PPAR[alpha]-cyclophilin D interaction in cardiomyocytes

AMP kinase (AMPK) plays an important role in the regulation of energy metabolism in cardiac cells. Furthermore, activation of AMPK protects the heart from myocardial infarction and heart failure. The present study examines whether or not AMPK affects the peroxisome proliferator-activated receptor-α...

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Bibliographic Details
Published in:American journal of physiology. Heart and circulatory physiology 2015-04, Vol.308 (7), p.H749
Main Authors: Barreto-Torres, Giselle, Hernandez, Jessica Soto, Jang, Sehwan, Rodríguez-Muñoz, Adlín R, Torres-Ramos, Carlos A, Basnakian, Alexei G, Javadov, Sabzali
Format: Article
Language:English
Subjects:
Effects
Heart
Kinases
Mitochondria
Oxidative stress
Permeability
Phosphorylation
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Summary:AMP kinase (AMPK) plays an important role in the regulation of energy metabolism in cardiac cells. Furthermore, activation of AMPK protects the heart from myocardial infarction and heart failure. The present study examines whether or not AMPK affects the peroxisome proliferator-activated receptor-α (PPARα)/mitochondria pathway in response to acute oxidative stress in cultured cardiomyocytes. Cultured H9c2 rat embryonic cardioblasts were exposed to H...O...-induced acute oxidative stress in the presence or absence of metformin, compound C (AMPK inhibitor), GW6471 (PPARα inhibitor), or A-769662 (AMPK activator). Results showed that AMPK activation by metformin reverted oxidative stress-induced inactivation of AMPK and prevented oxidative stress-induced cell death. In addition, metformin attenuated reactive oxygen species generation and depolarization of the inner mitochondrial membrane. The antioxidative effects of metformin were associated with the prevention of mitochondrial DNA damage in cardiomyocytes. Coimmunoprecipitation studies revealed that metformin abolished oxidative stress-induced physical interactions between PPAR... and cyclophilin D (CypD), and the abolishment of these interactions was associated with inhibition of permeability transition pore formation. The beneficial effects of metformin were not due to acetylation or phosphorylation of PPARα in response to oxidative stress. In conclusion, this study demonstrates that the protective effects of metformin-induced AMPK activation against oxidative stress converge on mitochondria and are mediated, at least in part, through the dissociation of PPARα-CypD interactions, independent of phosphorylation and acetylation of PPARα and CypD. (ProQuest: ... denotes formulae/symbols omitted.)
ISSN:0363-6135
1522-1539