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, Wen Cheng Su, Yen Ling Sung, Yenn Jiang Lin, Shih Lin Chang, Li Wei Lo, 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 (US)
Article number38894
JournalScientific Reports
Volume6
DOIs
StatePublished - Dec 14 2016
Externally publishedYes

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Cite this

Weng, C. H., Chung, F. P., Chen, Y. C., Lin, S-F., Huang, P. H., Kuo, T. B. J., Hsu, W. H., Su, W. C., Sung, Y. L., Lin, Y. J., Chang, S. L., Lo, 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