An increased matrix metalloprotease9 (MMP9) during post-myocardial infarction (post-MI) exacerbates ischemia-induced chronic heart failure (CHF). Autophagy is cardioprotective during CHF, however, whether increased MMP9 suppressed autophagic activity in CHF is unknown. This study aimed to determine whether the increased MMP9 suppressed autophagic flux, and MMP9 inhibition increased autophagic flux in the heart of rats with Post-MI CHF. Sprague-Dawley rats underwent either Sham or coronary artery ligation, 6-8 weeks prior to being treated with MMP9-inhibitor for 7days, followed by cardiac autophagic flux measurement using lysosomal inhibitor BafilomycinA1. Further, autophagic flux was measured in vitro by treating H9c2 cardiomyocytes with two independent pharmacological MMP9 inhibitors, Salvianolic-Acid-B (SalB) or MMP9-inhibitor-I, and CRISPR/cas9-mediated MMP9 genetic ablation. CHF rats showed cardiac infarct, significantly increased left ventricular end-diastolic pressure (LVEDP), and increased MMP9 activity and fibrosis in the peri-infarct areas of left-ventricular myocardium. The autophagic markers LC3B-II and p62 measurement with lysosomal inhibition showed decreased autophagic flux in the peri-infarct myocardium. Treatment with SalB for 7days in CHF rats decreased MMP9 activity, cardiac fibrosis, and increased autophagic flux in the peri-infarct myocardium. As an in vitro corollary study, measurement of autophagic flux in H9c2 cardiomyocytes and fibroblasts showed that pharmacological inhibition or genetic ablation of MMP9 upregulates autophagic flux. These data are consistent with our observations that MMP9 inhibition upregulates autophagic flux in the heart of rats with CHF. In conclusion, the results in this study suggest that the beneficial outcome of MMP9 inhibition on pathological cardiac remodeling is in part mediated by improved autophagic flux.

中文翻译：

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MMP9抑制增加慢性心力衰竭的自噬通量

心肌梗塞后（MI 后）期间基质金属蛋白酶 9 (MMP9) 的增加会加剧缺血引起的慢性心力衰竭 (CHF)。自噬在 CHF 期间具有心脏保护作用，然而，MMP9 增加是否抑制 CHF 中的自噬活性尚不清楚。本研究旨在确定增加的 MMP9 是否抑制自噬通量，以及 MMP9 抑制是否增加了 MI 后 CHF 大鼠心脏中的自噬通量。Sprague-Dawley 大鼠在接受 MMP9 抑制剂治疗 7 天前 6-8 周接受假手术或冠状动脉结扎，然后使用溶酶体抑制剂 BafilomycinA1 测量心脏自噬通量。此外，通过用两种独立的药理学 MMP9 抑制剂丹酚酸-B (SalB) 或 MMP9-抑制剂-I 处理 H9c2 心肌细胞，在体外测量自噬通量，和 CRISPR/cas9 介导的 MMP9 基因消融。CHF 大鼠出现心肌梗塞，左心室舒张末压 (LVEDP) 显着升高，左心室心肌梗塞周围区域的 MMP9 活性和纤维化增加。溶酶体抑制的自噬标志物 LC3B-II 和 p62 测量显示梗塞周围心肌中的自噬通量降低。在 CHF 大鼠中用 SalB 治疗 7 天可降低 MMP9 活性、心脏纤维化，并增加梗塞周围心肌中的自噬通量。作为一项体外推论研究，对 H9c2 心肌细胞和成纤维细胞中自噬通量的测量表明，MMP9 的药理抑制或基因消融可上调自噬通量。这些数据与我们的观察一致，即 MMP9 抑制上调 CHF 大鼠心脏中的自噬通量。总之，本研究的结果表明 MMP9 抑制对病理性心脏重构的有益结果部分是由自噬通量改善介导的。