5型磷酸二酯酶通过调控基质金属蛋白酶-2的表达促进心肌梗死后心脏破裂的作用与机制研究

心脏破裂（CR）是急性心肌梗死（AMI）的致死性并发症。研究表明，基质金属蛋白酶（MMPs）激活导致的心肌细胞外基质降解是CR发生的关键。然而，MMPs在AMI中如何被激活仍不清楚。我们的研究发现：5型磷酸二酯酶（PDE5）在AMI早期的小鼠心肌中表达升高；PDE5抑制剂显著抑制心肌细胞缺氧诱导的MMP-2表达。由此，我们猜想PDE5是AMI中MMP-2被激活并导致CR的关键点。本项目拟在心肌特异性PDE5转基因小鼠和PDE5抑制剂干预的普通小鼠的CR模型中，研究PDE5促进CR的作用及机制。随后，利用重组腺相关病毒介导的siRNA-MMP-2转染PDE5转基因小鼠，研究MMP-2在PDE5促进CR中的作用。最后，用PDE5抑制剂、蛋白激酶G抑制剂干预心肌细胞，研究PDE5调控MMP-2表达的机制。本项目将阐明PDE5通过调控MMP-2的表达促进CR的全新机制，为CR的治疗提供新靶点。

Cardiac rupture (CR) represents a catastrophic complication of acute myocardial infarction (AMI). Researches showed that AMI-induced matrix metalloproteinases (MMPs) degradate myocardium extracellular matrix and play important roles in CR. But the mechanisms for AMI-induced MMPs are still not clear. Our previous study found that the expression of phosphodiesterase 5 (PDE5) was increased in the early stage of AMI in mice and PDE5 inhibitor significantly suppressed hypoxia-induced MMP-2 in cardiomyocytes. We hypothesized that PDE5 promotes the occurrence of CR by modulating MMP-2. In this project, cardiac-specific PDE5 transgenic mice and normal mice of PDE5 inhibitor intervention were used to establish animal model of CR，on which we study the effect and mechanisms of PDE5 promoting the occurrence of CR. Secondly, the PDE5 transgenic mice infected by recombinant adeno-associated virus (rAAV)-siRNA-MMP-2 was used to study the effect of MMP-2 on PDE5 promoting CR. Furthermore, PDE5 inhibitor and protein kinase G inhibitor were used to treat cardiomyocytes to reveal the meahanisms of PDE5 modulating MMP-2. This work will clarify the new mechanism of PDE5 participating in CR, and provide new strategies and targets for CR therapy.