Pleiotropic Effects of Myocardial MMP-9 Inhibition to Prevent Ventricular Arrhythmia
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 involveme...
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| Veröffentlicht in: | Scientific reports 2016-12, Vol.6 (1), p.38894-38894, Article 38894 |
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| creator | 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 |
| description | 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. |
| doi_str_mv | 10.1038/srep38894 |
| format | Article |
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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</creator><creatorcontrib>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</creatorcontrib><description>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.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/srep38894</identifier><identifier>PMID: 27966586</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>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 (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 ; 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</subject><ispartof>Scientific reports, 2016-12, Vol.6 (1), p.38894-38894, Article 38894</ispartof><rights>The Author(s) 2016</rights><rights>Copyright Nature Publishing Group Dec 2016</rights><rights>Copyright © 2016, The Author(s) 2016 The Author(s)</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c504t-1fb7d210d73541301a281d1c22a89779228e96584871aed6bd11e3b3d2da467f3</citedby><cites>FETCH-LOGICAL-c504t-1fb7d210d73541301a281d1c22a89779228e96584871aed6bd11e3b3d2da467f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5155273/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5155273/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,725,778,782,862,883,27907,27908,41103,42172,51559,53774,53776</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27966586$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Weng, Ching-Hui</creatorcontrib><creatorcontrib>Chung, Fa-Po</creatorcontrib><creatorcontrib>Chen, Yao-Chang</creatorcontrib><creatorcontrib>Lin, Shien-Fong</creatorcontrib><creatorcontrib>Huang, Po-Hsun</creatorcontrib><creatorcontrib>Kuo, Terry B. J.</creatorcontrib><creatorcontrib>Hsu, Wei-Hsuan</creatorcontrib><creatorcontrib>Su, Wen-Cheng</creatorcontrib><creatorcontrib>Sung, Yen-Ling</creatorcontrib><creatorcontrib>Lin, Yenn-Jiang</creatorcontrib><creatorcontrib>Chang, Shih-Lin</creatorcontrib><creatorcontrib>Lo, Li-Wei</creatorcontrib><creatorcontrib>Yeh, Hung-I</creatorcontrib><creatorcontrib>Chen, Yi-Jen</creatorcontrib><creatorcontrib>Hong, Yi-Ren</creatorcontrib><creatorcontrib>Chen, Shih-Ann</creatorcontrib><creatorcontrib>Hu, Yu-Feng</creatorcontrib><title>Pleiotropic Effects of Myocardial MMP-9 Inhibition to Prevent Ventricular Arrhythmia</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>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.</description><subject>14/19</subject><subject>64/110</subject><subject>692/4019/592/75/29/1873</subject><subject>692/699/75/29</subject><subject>82/29</subject><subject>Angiotensin</subject><subject>Angiotensin II</subject><subject>Angiotensin II - genetics</subject><subject>Angiotensin II - metabolism</subject><subject>Animals</subject><subject>Arrhythmia</subject><subject>Arrhythmias, Cardiac - enzymology</subject><subject>Arrhythmias, Cardiac - genetics</subject><subject>Arrhythmias, Cardiac - pathology</subject><subject>Arrhythmias, Cardiac - prevention & control</subject><subject>Calcium (reticular)</subject><subject>Calcium - metabolism</subject><subject>Calcium homeostasis</subject><subject>Calcium Signaling</subject><subject>Calcium signalling</subject><subject>Cardiomyocytes</subject><subject>Cyclic AMP-Dependent Protein Kinases - genetics</subject><subject>Cyclic AMP-Dependent Protein Kinases - metabolism</subject><subject>Gelatinase B</subject><subject>Homeostasis</subject><subject>Humanities and Social Sciences</subject><subject>Kinases</subject><subject>Leakage</subject><subject>Matrix metalloproteinase</subject><subject>Matrix Metalloproteinase 9 - deficiency</subject><subject>Matrix Metalloproteinase 9 - metabolism</subject><subject>Metalloproteinase</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>multidisciplinary</subject><subject>Myocardium - enzymology</subject><subject>Myocardium - pathology</subject><subject>Phosphorylation</subject><subject>Pluripotency</subject><subject>Protein kinase A</subject><subject>Rodents</subject><subject>Ryanodine Receptor Calcium Release Channel - genetics</subject><subject>Ryanodine Receptor Calcium Release Channel - metabolism</subject><subject>Sarcoplasmic reticulum</subject><subject>Science</subject><subject>Serine</subject><subject>Stem cells</subject><subject>Ventricle</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNplkUFrGzEUhEVpiE2SQ_5AEfTSBrZZPa1W0qUQQpIGbOJDkqvQSlpbYb1ypd2A_30VnBi3fQc9wXyMRgxC56T8QUoqLlN0GyqErD6hKZQVK4ACfD64T9BZSi9lHgayIvIYTYDLumainqLHRed8GGLYeINv2taZIeHQ4vk2GB2t1x2ezxeFxPf9yjd-8KHHQ8CL6F5dP-DnfERvxk5HfBXjajus1l6foqNWd8mdve8T9HR783j9q5g93N1fX80Kw8pqKEjbcAuktJyyitCSaBDEEgOgheRcAggnc8xKcKKdrRtLiKMNtWB1VfOWnqCfO9_N2KydNW9hdKc20a913Kqgvfpb6f1KLcOrYoQx4DQbfHs3iOH36NKg1j4Z13W6d2FMighGQADjkNGv_6AvYYx9_l6mpKQcgMlMfd9RJoaUm2n3YUip3upS-7oy--Uw_Z78KCcDFzsgZalfunjw5H9ufwC2BZ5D</recordid><startdate>20161214</startdate><enddate>20161214</enddate><creator>Weng, Ching-Hui</creator><creator>Chung, Fa-Po</creator><creator>Chen, Yao-Chang</creator><creator>Lin, Shien-Fong</creator><creator>Huang, Po-Hsun</creator><creator>Kuo, Terry B. 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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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c504t-1fb7d210d73541301a281d1c22a89779228e96584871aed6bd11e3b3d2da467f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>14/19</topic><topic>64/110</topic><topic>692/4019/592/75/29/1873</topic><topic>692/699/75/29</topic><topic>82/29</topic><topic>Angiotensin</topic><topic>Angiotensin II</topic><topic>Angiotensin II - genetics</topic><topic>Angiotensin II - metabolism</topic><topic>Animals</topic><topic>Arrhythmia</topic><topic>Arrhythmias, Cardiac - enzymology</topic><topic>Arrhythmias, Cardiac - genetics</topic><topic>Arrhythmias, Cardiac - pathology</topic><topic>Arrhythmias, Cardiac - prevention & control</topic><topic>Calcium (reticular)</topic><topic>Calcium - metabolism</topic><topic>Calcium homeostasis</topic><topic>Calcium Signaling</topic><topic>Calcium signalling</topic><topic>Cardiomyocytes</topic><topic>Cyclic AMP-Dependent Protein Kinases - genetics</topic><topic>Cyclic AMP-Dependent Protein Kinases - metabolism</topic><topic>Gelatinase B</topic><topic>Homeostasis</topic><topic>Humanities and Social Sciences</topic><topic>Kinases</topic><topic>Leakage</topic><topic>Matrix metalloproteinase</topic><topic>Matrix Metalloproteinase 9 - deficiency</topic><topic>Matrix Metalloproteinase 9 - metabolism</topic><topic>Metalloproteinase</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>multidisciplinary</topic><topic>Myocardium - enzymology</topic><topic>Myocardium - pathology</topic><topic>Phosphorylation</topic><topic>Pluripotency</topic><topic>Protein kinase A</topic><topic>Rodents</topic><topic>Ryanodine Receptor Calcium Release Channel - genetics</topic><topic>Ryanodine Receptor Calcium Release Channel - metabolism</topic><topic>Sarcoplasmic reticulum</topic><topic>Science</topic><topic>Serine</topic><topic>Stem cells</topic><topic>Ventricle</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Weng, Ching-Hui</creatorcontrib><creatorcontrib>Chung, Fa-Po</creatorcontrib><creatorcontrib>Chen, Yao-Chang</creatorcontrib><creatorcontrib>Lin, Shien-Fong</creatorcontrib><creatorcontrib>Huang, Po-Hsun</creatorcontrib><creatorcontrib>Kuo, Terry B. 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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.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>27966586</pmid><doi>10.1038/srep38894</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| 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 (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 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 |
| title | Pleiotropic Effects of Myocardial MMP-9 Inhibition to Prevent Ventricular Arrhythmia |
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