Overexpression of A kinase interacting protein 1 attenuates myocardial ischaemia/reperfusion injury but does not influence heart failure development

Cardiovasc Res. 2016 Aug 1;111(3):217-26. doi: 10.1093/cvr/cvw161. Epub 2016 Jun 14.


Aims: A kinase interacting protein 1 (AKIP1) stimulates physiological growth in cultured cardiomyocytes and attenuates ischaemia/reperfusion (I/R) injury in ex vivo perfused hearts. We aimed to determine whether AKIP1 modulates the cardiac response to acute and chronic cardiac stresses in vivo.

Methods and results: Transgenic mice with cardiac-specific overexpression of AKIP1 (AKIP1-TG) were created. AKIP1-TG mice and their wild-type (WT) littermates displayed similar cardiac structure and function. Likewise, cardiac remodelling in response to transverse aortic constriction or permanent coronary artery ligation was identical in AKIP1-TG and WT littermates, as evidenced by serial cardiac magnetic resonance imaging and pressure-volume loop analysis. Histological indices of remodelling, including cardiomyocyte cross-sectional diameter, capillary density, and left ventricular fibrosis were also similar in AKIP1-TG mice and WT littermates. When subjected to 45 min of ischaemia followed by 24 h of reperfusion, AKIP1-TG mice displayed a significant two-fold reduction in myocardial infarct size and reductions in cardiac apoptosis. In contrast to previous reports, AKIP1 did not co-immunoprecipitate with or regulate the activity of the signalling molecules NF-κB, protein kinase A, or AKT. AKIP1 was, however, enriched in cardiac mitochondria and co-immunoprecipitated with a key component of the mitochondrial permeability transition (MPT) pore, ATP synthase. Finally, mitochondria isolated from AKIP1-TG hearts displayed markedly reduced calcium-induced swelling, indicative of reduced MPT pore formation.

Conclusions: In contrast to in vitro studies, AKIP1 overexpression does not influence cardiac remodelling in response to chronic cardiac stress. AKIP1 does, however, reduce myocardial I/R injury through stabilization of the MPT pore. These findings suggest that AKIP1 deserves further investigation as a putative treatment target for cardioprotection from I/R injury during acute myocardial infarction.

Keywords: AKIP1; Heart failure; Hypertrophy; Mitochondrial permeability transition pore; Reperfusion injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Apoptosis
  • Cells, Cultured
  • Disease Models, Animal
  • Disease Progression
  • Fibrosis
  • Genetic Predisposition to Disease
  • Heart Failure / enzymology*
  • Heart Failure / genetics
  • Heart Failure / physiopathology
  • Hemodynamics
  • Hypertrophy, Left Ventricular / enzymology
  • Hypertrophy, Left Ventricular / genetics
  • Hypertrophy, Left Ventricular / physiopathology
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitochondria, Heart / enzymology
  • Mitochondrial Membrane Transport Proteins / metabolism
  • Mitochondrial Swelling
  • Myocardial Infarction / enzymology
  • Myocardial Infarction / genetics
  • Myocardial Infarction / physiopathology
  • Myocardial Infarction / prevention & control*
  • Myocardial Reperfusion Injury / enzymology
  • Myocardial Reperfusion Injury / genetics
  • Myocardial Reperfusion Injury / physiopathology
  • Myocardial Reperfusion Injury / prevention & control*
  • Myocytes, Cardiac / enzymology*
  • Myocytes, Cardiac / pathology
  • Myosin Heavy Chains / genetics
  • Phenotype
  • Poly A / genetics
  • Promoter Regions, Genetic
  • Rats
  • Time Factors
  • Up-Regulation
  • Ventricular Function, Left
  • Ventricular Remodeling


  • AKIP1 protein, mouse
  • Adaptor Proteins, Signal Transducing
  • Mitochondrial Membrane Transport Proteins
  • mitochondrial permeability transition pore
  • Poly A
  • Myosin Heavy Chains