期刊
CARDIOVASCULAR RESEARCH
卷 102, 期 3, 页码 396-406出版社
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvu068
关键词
CnA beta 1; Calcineurin; Myocardial infarction; Cardiac remodelling; Akt
资金
- European Union [ERG-239158, CardioNeT-ITN-289600]
- Spanish Ministry of Science and Innovation [BFU2009-10016, SAF2012-31451]
- Regional Government of Madrid [2010-BMD-2321]
- Fondo de Investigaciones Sanitarias [RD12/0042/0066]
- Spanish Ministry of Economy and Competitiveness
- Pro-CNIC Foundation
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, CnA beta 1, 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 CnA beta 1 overexpression post-infarction. Double transgenic mice with inducible cardiomyocyte-specific overexpression of CnA beta 1 underwent left coronary artery ligation followed by reperfusion. Echocardiographic analysis showed depressed cardiac function in all infarcted mice 3 days post-infarction. Induction of CnA beta 1 overexpression 1 week after infarction improved function and reduced ventricular dilatation. CnA beta 1-overexpressing mice showed shorter, thicker scars, and reduced infarct expansion, accompanied by reduced myocardial remodelling. CnA beta 1 induced vascular endothelial growth factor (VEGF) expression in cardiomyocytes, which resulted in increased infarct vascularization. This paracrine angiogenic effect of CnA beta 1 was mediated by activation of the Akt/mammalian target of rapamycin pathway and VEGF. Our results indicate that CnA beta 1 exerts beneficial effects on the infarcted heart by promoting infarct vascularization and preventing infarct expansion. These findings emphasize the translational potential of CnA beta 1 for gene-based therapies.
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