title: Pleiotropic Effects of Myocardial MMP-9 Inhibition to Prevent Ventricular Arrhythmia.
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.
authors.affiliation: Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Ching-Hui
authors.initials: CH
authors.lastname: Weng
authors.affiliation: Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.|Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Fa-Po
authors.initials: FP
authors.lastname: Chung
authors.affiliation: Department of Biomedical Engineering, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Yao-Chang
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Institute of Biomedical Engineering, National Chiao-Tung University, Hsinchu, Taiwan.
authors.forename: Shien-Fong
authors.initials: SF
authors.lastname: Lin
authors.affiliation: Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.|Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Po-Hsun
authors.initials: PH
authors.lastname: Huang
authors.affiliation: Institute of Brain Science, National Yang Ming University, Taipei, Taiwan.
authors.forename: Terry B J
authors.initials: TB
authors.lastname: Kuo
authors.affiliation: Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Wei-Hsuan
authors.initials: WH
authors.lastname: Hsu
authors.affiliation: Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Su
authors.affiliation: Institute of Biomedical Engineering, National Chiao-Tung University, Hsinchu, Taiwan.
authors.forename: Yen-Ling
authors.initials: YL
authors.lastname: Sung
authors.affiliation: Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.|Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yenn-Jiang
authors.initials: YJ
authors.lastname: Lin
authors.affiliation: Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.|Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Shih-Lin
authors.initials: SL
authors.lastname: Chang
authors.affiliation: Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.|Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Li-Wei
authors.initials: LW
authors.lastname: Lo
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Mackay Memorial Hospital, Mackay Medical College, Taipei, Taiwan.
authors.forename: Hung-I
authors.initials: HI
authors.lastname: Yeh
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei Taiwan.
authors.forename: Yi-Jen
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Faculty of Medicine, Department of Biochemistry, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yi-Ren
authors.initials: YR
authors.lastname: Hong
authors.affiliation: Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.|Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Shih-Ann
authors.initials: SA
authors.lastname: Chen
authors.affiliation: Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.|Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yu-Feng
authors.initials: YF
authors.lastname: Hu
mesh_terms: D000804:Angiotensin II / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D000804:Angiotensin II; D017868:Cyclic AMP-Dependent Protein Kinases; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D002118:Calcium