{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T16:01:42Z","timestamp":1791388902384,"version":"4.3.3"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2018,6,20]],"date-time":"2018-06-20T00:00:00Z","timestamp":1529452800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01HL094404"],"award-info":[{"award-number":["R01HL094404"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01HL116525"],"award-info":[{"award-number":["R01HL116525"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["K01AG041208"],"award-info":[{"award-number":["K01AG041208"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01HL136292"],"award-info":[{"award-number":["R01HL136292"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University of Missouri System Research Board"},{"name":"University of Missouri School of Medicine Research Fellowship"},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Aims<\/jats:title><jats:p>Cardiomyocyte Ca2+ homeostasis is altered with aging via poorly-understood mechanisms. The Transient Receptor Potential Vanilloid 4 (TRPV4) ion channel is an osmotically-activated Ca2+ channel, and there is limited information on the role of TRPV4 in cardiomyocytes. Our data show that TRPV4 protein expression increases in cardiomyocytes of the aged heart. The objective of this study was to examine the role of TRPV4 in cardiomyocyte Ca2+ homeostasis following hypoosmotic stress and to assess the contribution of TRPV4 to cardiac contractility and tissue damage following ischaemia\u2013reperfusion (I\/R), a pathological condition associated with cardiomyocyte osmotic stress.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p>TRPV4 protein expression increased in cardiomyocytes of Aged (24\u201327\u2009months) mice compared with Young (3\u20136\u2009months) mice. Immunohistochemistry revealed TRPV4 localization to microtubules and the t-tubule network of cardiomyocytes of Aged mice, as well as in left ventricular myocardium of elderly patients undergoing surgical aortic valve replacement for aortic stenosis. Following hypoosmotic stress, cardiomyocytes of Aged, but not Young exhibited an increase in action-potential induced Ca2+ transients. This effect was mediated via increased sarcoplasmic reticulum Ca2+ content and facilitation of Ryanodine Receptor Ca2+ release and was prevented by TRPV4 antagonism (1\u2009\u03bcmol\/L HC067047). A similar hypoosmotic stress-induced facilitation of Ca2+ transients was observed in Young transgenic mice with inducible TRPV4 expression in cardiomyocytes. Following I\/R, isolated hearts of Young mice with transgenic TRPV4 expression exhibited enhanced contractility vs. hearts of Young control mice. Similarly, hearts of Aged mice exhibited enhanced contractility vs. hearts of Aged TRPV4 knock-out (TRPV4\u2212\/\u2212) mice. In Aged, pharmacological inhibition of TRPV4 (1\u2009\u03bcmol\/L, HC067047) prevented hypoosmotic stress-induced cardiomyocyte death and I\/R-induced cardiac damage.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings provide a new mechanism for hypoosmotic stress-induced cardiomyocyte Ca2+ entry and cell damage in the aged heart. These finding have potential implications in treatment of elderly populations at increased risk of myocardial infarction and I\/R injury.<\/jats:p><\/jats:sec>","DOI":"10.1093\/cvr\/cvy156","type":"journal-article","created":{"date-parts":[[2018,6,15]],"date-time":"2018-06-15T19:37:12Z","timestamp":1529091432000},"page":"46-56","source":"Crossref","is-referenced-by-count":84,"title":["TRPV4 increases cardiomyocyte calcium cycling and contractility yet contributes to damage in the aged heart following hypoosmotic stress"],"prefix":"10.1093","volume":"115","author":[{"given":"John L","family":"Jones","sequence":"first","affiliation":[{"name":"Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, 1 Hospital Drive, Columbia, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Peana","sequence":"additional","affiliation":[{"name":"Department of Medical Pharmacology and Physiology, University of Missouri School 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