Pleiotropic Effects of Myocardial MMP-9 Inhibition to Prevent Ventricular Arrhythmia

Ching Hui Weng, Fa Po Chung, Yao Chang Chen, Shien Fong Lin, Po Hsun Huang, Terry B J Kuo, Wei Hsuan Hsu, Cheng Wen Su, Yen Ling Sung, Yenn Jiang Lin, Shih Lin Chang, Li Wei Chou, Hung I. Yeh, Yi-Jen Chen, Yi Ren Hong, Shih Ann Chen, Yu Feng Hu

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Abstract

Observational studies have established a strong association between matrix metalloproteinase-9 (MMP-9) and ventricular arrhythmia. However, whether MMP-9 has a causal link to ventricular arrhythmia, as well as the underlying mechanism, remains unclear. Here, we investigated the mechanistic involvement of myocardial MMP-9 in the pathophysiology of ventricular arrhythmia. Increased levels of myocardial MMP-9 are linked to ventricular arrhythmia attacks after angiotensin II (Ang II) treatment. MMP-9-deficient mice were protected from ventricular arrhythmia. Increased expressions of protein kinase A (PKA) and ryanodine receptor phosphorylation at serine 2808 (pS2808) were correlated with inducible ventricular arrhythmia. MMP-9 deficiency consistently prevented PKA and pS2808 increases after Ang II treatment and reduced ventricular arrhythmia. Calcium dynamics were examined via confocal imaging in isolated murine cardiomyocytes. MMP-9 inhibition prevents calcium leakage from the sarcoplasmic reticulum and reduces arrhythmia-like irregular calcium transients via protein kinase A and ryanodine receptor phosphorylation. Human induced pluripotent stem cell-derived cardiomyocytes similarly show that MMP-9 inhibition prevents abnormal calcium leakage. Myocardial MMP-9 inhibition prevents ventricular arrhythmia through pleiotropic effects, including the modulation of calcium homeostasis and reduced calcium leakage.

Original languageEnglish
Article number38894
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - Dec 14 2016

ASJC Scopus subject areas

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    Weng, C. H., Chung, F. P., Chen, Y. C., Lin, S. F., Huang, P. H., Kuo, T. B. J., Hsu, W. H., Su, C. W., Sung, Y. L., Lin, Y. J., Chang, S. L., Chou, L. W., Yeh, H. I., Chen, Y-J., Hong, Y. R., Chen, S. A., & Hu, Y. F. (2016). Pleiotropic Effects of Myocardial MMP-9 Inhibition to Prevent Ventricular Arrhythmia. Scientific Reports, 6, [38894]. https://doi.org/10.1038/srep38894