Induction of the calcineurin variant CnAβ1 after myocardial infarction reduces post-infarction ventricular remodelling by promoting infarct vascularization
Induction of the calcineurin variant CnAβ1 after myocardial infarction reduces post-infarction ventricular remodelling by promoting infarct vascularization
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DOI：
10.1093/cvr/cvu068
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发表时间：
2014-06-01
影响因子：
10.8
通讯作者：
Lara-Pezzi, Enrique
中科院分区：
文献类型：
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作者：
Lopez-Olaneta, Marina M.;Villalba, Maria;Lara-Pezzi, Enrique
心肌梗死后的心室重构逐渐导致收缩能力的丧失和心力衰竭。虽然钙调神经磷酸酶促进适应性不良的心肌肥厚，但我们最近发现，钙调神经磷酸酶剪接变异体CNAβ1对梗死心脏有有益的影响。然而，这种变异是否限制了坏死或改善了重塑仍是未知的，排除了转化到临床领域的可能性。在这里，我们探讨了心肌梗死后CNAβ1过度表达的效果和治疗潜力。双转基因小鼠可诱导心肌细胞特异性CNAβ1过表达，并接受左冠状动脉结扎后再灌注。超声心动图分析显示，所有梗死小鼠在梗死后3天心功能均受到抑制。心肌梗死后1周诱导CNAβ1过度表达可改善功能，减少心室扩张。CNAβ1过表达的小鼠显示出更短、更厚的疤痕，并减少了梗塞扩大，并伴随着减少的心肌重塑。CNAβ1诱导心肌细胞表达血管内皮生长因子，导致心肌梗死血管形成增加。CNAβ1的这种旁分泌血管生成作用是通过激活Akt/哺乳动物靶点雷帕霉素途径和血管内皮生长因子来实现的。我们的研究结果表明，CNAβ1通过促进梗塞血管形成和防止梗塞扩大而对梗塞心脏起到有益的作用。这些发现强调了CNA beta 1在基于基因的治疗中的翻译潜力。
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.