Induction of the calcineurin variant CnAβ1 after myocardial infarction reduces post-infarction ventricular remodelling by promoting infarct vascularization

More about Open Access at the Crick

Abstract

Aims Ventricular remodelling following myocardial infarction progressively leads to loss of contractile capacity and heart failure. Although calcineurin promotes maladaptive cardiac hypertrophy, we recently showed that the calcineurin splicing variant CnAβ1 has beneficial effects on the infarcted heart. However, whether this variant limits necrosis or improves remodelling is still unknown, precluding translation to the clinical arena. Here we explored the effects and therapeutic potential of CnAβ1 overexpression post-infarction.Methods and Results Double transgenic mice with inducible cardiomyocyte-specific overexpression of CnAβ1 underwent left coronary artery ligation followed by reperfusion. Echocardiographic analysis showed depressed cardiac function in all infarcted mice 3 days post-infarction. Induction of CnAβ1 overexpression one week after infarction improved function and reduced ventricular dilatation. CnAβ1-overexpressing mice showed shorter, thicker scars and reduced infarct expansion, accompanied by reduced myocardial remodelling. CnAβ1 induced vascular endothelial growth factor (VEGF) expression in cardiomyocytes, which resulted in increased infarct vascularisation. This paracrine angiogenic effect of CnAβ1 was mediated by activation of the Akt/mTOR pathway and VEGF.Conclusions Our results indicate that CnAβ1 exerts beneficial effects on the infarcted heart by promoting infarct vascularisation and preventing infarct expansion. These findings highlight the translational potential of CnAβ1 for gene-based therapies.