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


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.


CONCLUSIONS
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.
Perrino
Cinzia
C
Department of Clinical Medicine, Cardiovascular and Immunological Sciences, Federico II University, Naples 80131, Italy. perrino@unina.it
Feliciello
Antonio
A
Schiattarella
Gabriele G
GG
Esposito
Giovanni
G
Guerriero
Rosalia
R
Zaccaro
Laura
L
Del Gatto
Annarita
A
Saviano
Michele
M
Garbi
Corrado
C
Carangi
Rosa
R
Di Lorenzo
Emilio
E
Donato
Giuseppe
G
Indolfi
Ciro
C
Avvedimento
Vittorio Enrico
VE
Chiariello
Massimo
M
D054758:A Kinase Anchor Proteins / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001667:Binding, Competitive; D002470:Cell Survival; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015290:Second Messenger Systems / Q000187:drug effects
D054758:A Kinase Anchor Proteins; C486333:Akap1 protein, mouse; C486332:Akap1 protein, rat; D010455:Peptides; D000242:Cyclic AMP