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

• Published in: Scientific reports Vol. 6; no. 1; p. 38894
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.12.2016; Nature Publishing Group
• Subjects: 14/19; 64/110; 692/4019/592/75/29/1873; 692/699/75/29; 82/29; Angiotensin; Angiotensin II; Angiotensin II - genetics; Angiotensin II - metabolism; Animals; Arrhythmia; Arrhythmias, Cardiac - enzymology; Arrhythmias, Cardiac - genetics; Arrhythmias, Cardiac - pathology; Arrhythmias, Cardiac - prevention & control; Calcium; Calcium (reticular); Calcium - metabolism; Calcium homeostasis; Calcium Signaling; Calcium signalling; Cardiomyocytes; Cyclic AMP-Dependent Protein Kinases - genetics; Cyclic AMP-Dependent Protein Kinases - metabolism; Gelatinase B; Homeostasis; Humanities and Social Sciences; Kinases; Leakage; Matrix metalloproteinase; Matrix Metalloproteinase 9 - deficiency; Matrix Metalloproteinase 9 - metabolism; Metalloproteinase; Mice; Mice, Knockout; multidisciplinary; Myocardium - enzymology; Myocardium - pathology; Observational studies; Phosphorylation; Pluripotency; Protein kinase A; Rodents; Ryanodine Receptor Calcium Release Channel - genetics; Ryanodine Receptor Calcium Release Channel - metabolism; Sarcoplasmic reticulum; Science; Serine; Stem cells; Ventricle
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep38894

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.