{"corpus_id":19014521,"paper_sha":"37aabbf5e2db0372421c0693c696e50a1de3a557","doi":"10.1038/srep38894","arxiv_id":null,"pmid":27966586,"pmcid":"5155273","mag_id":2564551377,"dblp_id":null,"acl_id":null,"title":"Pleiotropic Effects of Myocardial MMP-9 Inhibition to Prevent Ventricular Arrhythmia","year":2016,"publication_date":"2016-12-14","venue":"Scientific Reports","journal":{"name":"Scientific Reports","pages":null,"volume":"6"},"journal_issn":null,"journal_title":null,"publication_types":["JournalArticle"],"pubmed_pub_types":["Journal Article","Research Support, Non-U.S. Gov't"],"s2_fields_of_study":["Medicine","Chemistry"],"reference_count":59,"citation_count":23,"influential_citation_count":1,"is_open_access":true,"arxiv_categories":null,"arxiv_license":null,"arxiv_journal_ref":null,"mesh_headings":[{"d":"Angiotensin II","mj":false,"qs":[{"q":"genetics","mj":false,"ui":"Q000235"},{"q":"metabolism","mj":false,"ui":"Q000378"}],"ui":"D000804"},{"d":"Animals","mj":false,"ui":"D000818"},{"d":"Arrhythmias, Cardiac","mj":true,"qs":[{"q":"enzymology","mj":false,"ui":"Q000201"},{"q":"genetics","mj":false,"ui":"Q000235"},{"q":"pathology","mj":false,"ui":"Q000473"},{"q":"prevention & control","mj":false,"ui":"Q000517"}],"ui":"D001145"},{"d":"Calcium","mj":false,"qs":[{"q":"metabolism","mj":true,"ui":"Q000378"}],"ui":"D002118"},{"d":"Calcium Signaling","mj":true,"ui":"D020013"},{"d":"Cyclic AMP-Dependent Protein Kinases","mj":false,"qs":[{"q":"genetics","mj":false,"ui":"Q000235"},{"q":"metabolism","mj":false,"ui":"Q000378"}],"ui":"D017868"},{"d":"Matrix Metalloproteinase 9","mj":false,"qs":[{"q":"deficiency","mj":true,"ui":"Q000172"},{"q":"metabolism","mj":false,"ui":"Q000378"}],"ui":"D020780"},{"d":"Mice","mj":false,"ui":"D051379"},{"d":"Mice, Knockout","mj":false,"ui":"D018345"},{"d":"Myocardium","mj":false,"qs":[{"q":"enzymology","mj":true,"ui":"Q000201"},{"q":"pathology","mj":false,"ui":"Q000473"}],"ui":"D009206"},{"d":"Ryanodine Receptor Calcium Release Channel","mj":false,"qs":[{"q":"genetics","mj":false,"ui":"Q000235"},{"q":"metabolism","mj":false,"ui":"Q000378"}],"ui":"D019837"}],"chemicals":[{"n":"Ryanodine Receptor Calcium Release Channel","ui":"D019837","reg":"0"},{"n":"Angiotensin II","ui":"D000804","reg":"11128-99-7"},{"n":"Cyclic AMP-Dependent Protein Kinases","ui":"D017868","reg":"EC 2.7.11.11"},{"n":"Matrix Metalloproteinase 9","ui":"D020780","reg":"EC 3.4.24.35"},{"n":"Mmp9 protein, mouse","ui":"C501830","reg":"EC 3.4.24.35"},{"n":"Calcium","ui":"D002118","reg":"SY7Q814VUP"}],"comments_corrections":null,"source_flags":5,"s2_open_access_pdf_url":"https://www.nature.com/articles/srep38894.pdf","s2_open_access_landing_url":"https://www.semanticscholar.org/paper/37aabbf5e2db0372421c0693c696e50a1de3a557","s2_open_access_license":"CCBY","s2_open_access_status":"GOLD","pmc_open_access_pdf_url":null,"pmc_open_access_landing_url":null,"pmc_open_access_license":null,"pmc_open_access_status":null,"unpaywall_open_access_pdf_url":null,"unpaywall_open_access_landing_url":null,"unpaywall_open_access_license":null,"unpaywall_open_access_status":null,"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.","claims":[{"public_id":"cl_4139fb6cf3b58bf888841fc00632e54c","status":"active","text":"Increased myocardial MMP-9 is linked to ventricular arrhythmia attacks after angiotensin II treatment.","confidence":0.96,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_4139fb6cf3b58bf888841fc00632e54c"},{"public_id":"cl_65bda7c2bf57669fc914eb4fd30c3c01","status":"active","text":"MMP-9 deficiency protects mice from ventricular arrhythmia and reduces arrhythmia after angiotensin II treatment.","confidence":0.98,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous 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