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



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.



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.
Department of Cardiology, University Medical Center Groningen, University of Groningen, Experimental Cardiology Section HPC AB 43, PO Box 30.001, Groningen 9700 RB, The Netherlands.
Harmen G
HG
Booij
Department of Cardiology, University Medical Center Groningen, University of Groningen, Experimental Cardiology Section HPC AB 43, PO Box 30.001, Groningen 9700 RB, The Netherlands Department of Hematology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Hongjuan
H
Yu
Department of Cardiology, University Medical Center Groningen, University of Groningen, Experimental Cardiology Section HPC AB 43, PO Box 30.001, Groningen 9700 RB, The Netherlands.
Rudolf A
RA
De Boer
Central Animal Laboratory, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Cees W A
CW
van de Kolk
Department of Pediatrics, Molecular Genetics Section, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Bart
B
van de Sluis
Department of Pediatrics, Mayo Clinic, Rochester, MN, USA.
Jan M
JM
Van Deursen
Department of Cardiology, University Medical Center Groningen, University of Groningen, Experimental Cardiology Section HPC AB 43, PO Box 30.001, Groningen 9700 RB, The Netherlands.
Wiek H
WH
Van Gilst
Department of Cardiology, University Medical Center Groningen, University of Groningen, Experimental Cardiology Section HPC AB 43, PO Box 30.001, Groningen 9700 RB, The Netherlands.
Herman H W
HH
Silljé
Department of Cardiology, University Medical Center Groningen, University of Groningen, Experimental Cardiology Section HPC AB 43, PO Box 30.001, Groningen 9700 RB, The Netherlands b.d.westenbrink@umcg.nl.
B Daan
BD
Westenbrink
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D005355:Fibrosis; D020022:Genetic Predisposition to Disease; D006333:Heart Failure / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D006439:Hemodynamics; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000201:enzymology; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D008933:Mitochondrial Swelling; D009203:Myocardial Infarction / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics; D010641:Phenotype; D011061:Poly A / Q000235:genetics; D011401:Promoter Regions, Genetic; D051381:Rats; D013997:Time Factors; D015854:Up-Regulation; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
C000623337:AKIP1 protein, mouse; D048868:Adaptor Proteins, Signal Transducing; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D011061:Poly A; D018995:Myosin Heavy Chains
AKIP1; Heart failure; Hypertrophy; Mitochondrial permeability transition pore; Reperfusion injury