Key result
CnAβ1 overexpression one week post-MI improves cardiac function and reduces ventricular dilatation in mice.
Why the study?
Whether the calcineurin splicing variant CnAβ1 limits necrosis or improves ventricular remodelling after myocardial infarction was unknown, precluding clinical translation.
Does induction of CnAβ1 overexpression improve cardiac function and reduce ventricular remodelling in mice post-myocardial infarction?
Does induction of CnAβ1 overexpression improve cardiac function and reduce ventricular remodelling in mice post-myocardial infarction?
Overexpression of the calcineurin variant CnAβ1 post-infarction in mice improves cardiac function and reduces adverse remodelling by promoting infarct vascularization.
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 1 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 vascularization. This paracrine angiogenic effect of CnAβ1 was mediated by activation of the Akt/mammalian target of rapamycin pathway and VEGF. CONCLUSIONS: Our results indicate that CnAβ1 exerts beneficial effects on the infarcted heart by promoting infarct vascularization and preventing infarct expansion. These findings emphasize the translational potential of CnAβ1 for gene-based therapies.
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López‐Olañeta et al. (2014) studied Myocardial infarction. CnAβ1 overexpression was evaluated on Cardiac function and ventricular remodelling. Induction of CnAβ1 overexpression 1 week after myocardial infarction improved cardiac function, reduced ventricular dilatation, and promoted infarct vascularization in mice.
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