Introduction:
A kinase interacting protein 1 (AKIP1) attenuates myocardial ischemia / reperfusion (I/R) injury and stimulates beneficial cardiac remodeling in cultured cardiomyocytes. Whether these findings translate into functional benefits
in vivo
remains to be established.
Hypothesis:
We assessed the hypothesis that cardiac overexpression of AKIP1 attenuates myocardial heart failure development or I/R-injury in mice.
Methods:
We created transgenic mice with cardiac-specific overexpression of AKIP1 (AKIP1-TG). First, AKIP1-TG mice or their wild type littermates were subjected to transverse aortic constriction (TAC) and myocardial infarction (MI) with permanent ligation of the left coronary artery. Second, infarct size after 45 minutes ischemia followed by 24h reperfusion was assessed with Evans Bleu and triphenyltetrazolium chloride staining.
Results:
AKIP1-TG mice and wild type littermates displayed similar left ventricular remodeling and function after TAC or MI as measured with magnetic resonance imaging. Histological indices of heart failure severity, including cardiomyocyte cross-sectional area, capillary density and fibrosis were also similar. However, infarct size relative to the area at risk was reduced 2-fold in AKIP1-TG mice after I/R (15% ± 3 vs. 29± 4 %, p<0,05) and accompanied with a marked reduction in apoptosis (5,4 ± 0,5% vs. 8,1 ± 1,1%, p<0,05). AKIP1 overexpression did not influence cardiac transcription or signaling. Subcellular fraction studies showed enrichment of AKIP1 in mitochondria. In addition, AKIP1 attenuated calcium induced swelling of mitochondria (0.77 ± 0.01 vs. 0.71 ± 0.01, p<0.05), suggesting a direct role for AKIP1 in the mitochondrial permeability transition pore.
Conclusions:
In conclusion, AKIP1 does not influence cardiac remodeling in models of chronic heart failure. However, AKIP1 does attenuate myocardial I/R injury through stabilization of the mitochondrial permeability transition pore.
Heart failure–induced activation of phospholipase iPLA2γ generates hydroxyeicosatetraenoic acids opening the mitochondrial permeability transition pore
