Abstract 3508: Integrin Linked Kinase (ILK) is Cardioprotective Against Ischemia
Introduction: Integrin linked kinase (ILK) is a multifunctional protein kinase which regulates a wide variety of cellular functions such as hypertrophy, angiogenesis, migration, proliferation, motility and cell survival. The objective of this study was to investigate the role of ILK pathway targets in response to myocardial ischemia.
Methods: Human fetal cardiomyocytes were subjected to ischemia and the effect on ILK and its downstream targets was measured over time. We generated a mouse model overexpressing both the kinase active (ILK-A) and inactive (ILK-In) forms of ILK. We performed left anterior descending (LAD) coronary artery ligation on 32 mice: 8 each from the ILK-A and ILK-In groups and respective littermate controls. Echocardiograms were performed at baseline, 7 and 28 days post LAD ligation. Isovolumic relaxation time (IVRT) (diastolic) and isovolumic contraction time (IVCT) (systolic) measured global cardiac function; infarct size was determined by TTC staining. ILK and its interactors VEGF, PINCH, and hypoxia inducible factor (HIF-1α) were measured in the infarct/border zone.
Results: ILK expression in human fetal cardiomyocytes was elevated in response to ischemia peaking at 10 hours. ILK-A mice had smaller myocardial infarcts compared to both controls and ILK-In mice [(ANOVA) p <0.05]. ILK and HIF-1α were highly upregulated in the infarct zone compared to baseline (p<0.05) and especially in ILK-A. Echocardiograms showed significantly (*) improved function at 28 days.
Conclusion: Endogenous ILK activation occurs in response to ischemia in human cardiomyocytes in vitro and in hypoxic myocardium in vivo. It is associated with an increase in HIF-1α. Increased levels of activated ILK in the heart resulted in better global function following myocardial infarction in an animal model. Upregulation of this pathway to enhance cardiomyocyte survival represents a novel therapeutic approach to rescue vulnerable myocardium.