{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T12:04:44Z","timestamp":1792670684572,"version":"4.5.0"},"reference-count":57,"publisher":"American Physiological Society","issue":"4","funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2015R1C1A2A01052419"],"award-info":[{"award-number":["2015R1C1A2A01052419"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2017R1A2B2004085"],"award-info":[{"award-number":["2017R1A2B2004085"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2018R1D1A1B07042484"],"award-info":[{"award-number":["2018R1D1A1B07042484"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"published-print":{"date-parts":[[2020,4,1]]},"abstract":"<jats:p> A variant in the PRDM16 locus has been correlated with QRS duration in an electrocardiogram genome-wide association study, and the deletion of PRDM16 has been implicated as a causal factor of the dilated cardiomyopathy that is linked to 1p36 deletion syndrome. We aimed to determine how a null mutation of Prdm16 affects cardiac function and study the underlying mechanism of the resulting phenotype in an appropriate mouse model. We used cardiac-specific Prdm16 conditional knockout mice to examine cardiac function by electrocardiography. QRS duration and QTc interval increased significantly in cardiac-specific Prdm16 knockout animals compared with wild-type mice. Further, we assessed cardiomyopathy-associated features by trichrome staining, densitometry, and hydroxyproline assay. Prdm16-null hearts showed greater fibrosis and cardiomyocyte hypertrophy. By quantitative real-time PCR, Prdm16-null hearts upregulated extracellular matrix-related genes ( Ctgf, Timp1) and \u03b1-smooth muscle actin ( Acta2), a myofibroblast marker. Moreover, TGF-\u03b2 signaling was activated in Prdm16-null hearts, as evidenced by increased Tgfb1\u20133 transcript levels and phosphorylated Smad2. However, the inhibition of TGF-\u03b2 receptor did not reverse the aberrations in conduction in cardiac-specific Prdm16 knockout mice. To determine the underlying mechanisms, we performed RNA-seq using mouse left ventricular tissue. By functional analysis, Prdm16-null hearts experienced dysregulated expression of ion channel genes, including Kcne1, Scn5a, Cacna1h, and Cacna2d2. Mice with Prdm16-null hearts develop abnormalities in cardiac conduction and cardiomyopathy-associated phenotypes, including fibrosis and cellular hypertrophy. Further, the RNA-seq findings suggest that impairments in ion homeostasis (Ca<jats:sup>2+<\/jats:sup>, K<jats:sup>+<\/jats:sup>, and Na<jats:sup>+<\/jats:sup>) may at least partially underlie the abnormal conduction in cardiac-specific Prdm16 knockout mice. <\/jats:p><jats:p> NEW &amp; NOTEWORTHY This is the first study that describes aberrant cardiac function and cardiomyopathy-associated phenotypes in an appropriate murine genetic model with cardiomyocyte-specific Prdm16-null mutation. It is noteworthy that the correlation of PRDM16 with QRS duration is replicated in a murine animal model and the potential underlying mechanism may be the impairment of ion homeostasis. <\/jats:p>","DOI":"10.1152\/ajpheart.00647.2019","type":"journal-article","created":{"date-parts":[[2020,2,21]],"date-time":"2020-02-21T17:43:08Z","timestamp":1582306988000},"page":"H764-H777","source":"Crossref","is-referenced-by-count":34,"title":["Cardiac-specific inactivation of <i>Prdm16<\/i> effects cardiac conduction abnormalities and cardiomyopathy-associated phenotypes"],"prefix":"10.1152","volume":"318","author":[{"given":"Jeong Min","family":"Nam","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Eun","family":"Lim","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of 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