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AKAP121 downregulation impairs protective cAMP signals, promotes mitochondrial dysfunction, and increases oxidative stress

Item Type:Article
Title:AKAP121 downregulation impairs protective cAMP signals, promotes mitochondrial dysfunction, and increases oxidative stress
Creators Name:Perrino, C. and Feliciello, A. and Schiattarella, G.G. and Esposito, G. and Guerriero, R. and Zaccaro, L. and Del Gatto, A. and Saviano, M. and Garbi, C. and Carangi, R. and Di Lorenzo, E. and Donato, G. and Indolfi, C. and Avvedimento, V.E. and Chiariello, M.
Abstract:AIMS: The aim of the present study was to determine the function and the role of the scaffold protein AKAP121, tethering cAMP dependent protein kinase A to the outer wall of mitochondria, in neonatal ventricular myocytes and the heart. METHODS AND RESULTS: Competitive peptides displacing AKAP121 from mitochondria in the tissue and in the cells were used to investigate the role of AKAP121 in mitochondrial function, reactive oxygen species (ROS) generation, and cell survival. Displacement of AKAP121 from mitochondria by synthetic peptides triggers the death program in cardiomyocytes. Under pathological conditions in vivo, in a rat model of cardiac hypertrophy induced by ascending aorta banding, the levels of AKAP121 are significantly down-regulated. Disappearance of AKAP121 is associated with mitochondrial dysfunction, high oxidative stress, and apoptosis. In vivo delocalization of AKAP121 by competitive peptides replicates some of the molecular signatures induced by pressure overload: mitochondrial dysfunction, increased mitochondrial ROS, and apoptosis. CONCLUSION: These data suggest that AKAP121 regulates the response to stress in cardiomyocytes, and therefore AKAP121 downregulation might represent an important event contributing to the development of cardiac dysfunction.
Keywords:Mitochondria, Heart Failure, Protein Kinase A, Oxygen Radicals, Animals, Mice, Rats
Source:Cardiovascular Research
ISSN:0008-6363
Publisher:Oxford University Press
Volume:88
Number:1
Page Range:101-110
Date:1 October 2010
Official Publication:https://doi.org/10.1093/cvr/cvq155
PubMed:View item in PubMed

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