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

Proc Natl Acad Sci U S A. 2013 Jan 29;110(5):E387-96. doi: 10.1073/pnas.1221670110. Epub 2013 Jan 14.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Apoptosis Inducing Factor / metabolism
  • Blotting, Western
  • Cell Line, Tumor
  • Cells, Cultured
  • HEK293 Cells
  • HeLa Cells
  • Heart / physiology*
  • Heart / physiopathology
  • Humans
  • Hydrogen Peroxide / pharmacology
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Confocal
  • Mitochondria, Heart / metabolism
  • Myocardial Reperfusion Injury / physiopathology
  • Myocardium / cytology
  • Myocardium / metabolism*
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Oxidants / pharmacology
  • Protein Binding
  • Rats
  • Rats, Sprague-Dawley


  • AKIP1 protein, human
  • AKIP1 protein, rat
  • Adaptor Proteins, Signal Transducing
  • Apoptosis Inducing Factor
  • Nuclear Proteins
  • Oxidants
  • Hydrogen Peroxide