標題: Pleiotropic Effects of Myocardial MMP-9 Inhibition to Prevent Ventricular Arrhythmia
作者: Weng, Ching-Hui
Chung, Fa-Po
Chen, Yao-Chang
Lin, Shien-Fong
Huang, Po-Hsun
Kuo, Terry B. J.
Hsu, Wei-Hsuan
Su, Wen-Cheng
Sung, Yen-Ling
Lin, Yenn-Jiang
Chang, Shih-Lin
Lo, Li-Wei
Yeh, Hung-I
Chen, Yi-Jen
Hong, Yi-Ren
Chen, Shih-Ann
Hu, Yu-Feng
分子醫學與生物工程研究所
Institute of Molecular Medicine and Bioengineering
公開日期: 14-Dec-2016
摘要: 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.
URI: http://dx.doi.org/10.1038/srep38894
http://hdl.handle.net/11536/132740
ISSN: 2045-2322
DOI: 10.1038/srep38894
期刊: SCIENTIFIC REPORTS
Volume: 6
起始頁: 0
結束頁: 0
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