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A kinase interacting protein (AKIP1) is a key regulator of cardiac stress.

ABSTRACT: cAMP-dependent protein kinase (PKA) regulates a myriad of functions in the heart, including cardiac contractility, myocardial metabolism,and gene expression. However, a molecular integrator of the PKA response in the heart is unknown. Here, we show that the PKA adaptor A-kinase interacting protein 1 (AKIP1) is up-regulated in cardiac myocytes in response to oxidant stress. Mice with cardiac gene transfer of AKIP1 have enhanced protection to ischemic stress. We hypothesized that this adaptation to stress was mitochondrial dependent. AKIP1 interacted with the mitochondrial localized apoptosis inducing factor (AIF) under both normal and oxidant stress. When cardiac myocytes or whole hearts are exposed to oxidant and ischemic stress, levels of both AKIP1 and AIF were enhanced. AKIP1 is preferentially localized to interfibrillary mitochondria and up-regulated in this cardiac mitochondrial subpopulation on ischemic injury. Mitochondria isolated from AKIP1 gene transferred hearts showed increased mitochondrial localization of AKIP1, decreased reactive oxygen species generation, enhanced calcium tolerance, decreased mitochondrial cytochrome C release,and enhance phosphorylation of mitochondrial PKA substrates on ischemic stress. These observations highlight AKIP1 as a critical molecular regulator and a therapeutic control point for stress adaptation in the heart.

SUBMITTER: Sastri M

PROVIDER: S-EPMC3562788 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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A kinase interacting protein (AKIP1) is a key regulator of cardiac stress.

Sastri Mira M Haushalter Kristofer J KJ Panneerselvam Mathivadhani M Chang Philip P Fridolfsson Heidi H Finley J Cameron JC Ng Daniel D Schilling Jan M JM Miyanohara Atsushi A Day Michele E ME Hakozaki Hiro H Petrosyan Susanna S Koller Antonius A King Charles C CC Darshi Manjula M Blumenthal Donald K DK Ali Sameh Saad SS Roth David M DM Patel Hemal H HH Taylor Susan S SS

Proceedings of the National Academy of Sciences of the United States of America 20130114 5

cAMP-dependent protein kinase (PKA) regulates a myriad of functions in the heart, including cardiac contractility, myocardial metabolism,and gene expression. However, a molecular integrator of the PKA response in the heart is unknown. Here, we show that the PKA adaptor A-kinase interacting protein 1 (AKIP1) is up-regulated in cardiac myocytes in response to oxidant stress. Mice with cardiac gene transfer of AKIP1 have enhanced protection to ischemic stress. We hypothesized that this adaptation t ...[more]

PMID: 23319652

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A kinase interacting protein (AKIP1) is a key regulator of cardiac stress.

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A kinase interacting protein (AKIP1) is a key regulator of cardiac stress.

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