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To explore the same, NRK2 knockout (KO) and littermate control mice were subjected to trans-aortic constriction (TAC) or sham surgeries and cardiac function was assessed by serial M-mode echocardiography. A mild cardiac contractile dysfunction was observed in the KOs at the early adaptive phase of remodeling followed by a significant deterioration during the maladaptive cardiac remodeling phase. Consistently, NRK2 KO hearts displayed increased cardiac hypertrophy and heart failure (HF) reflected by morphometric parameters as well as increased fetal genes, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) expressions. Histological assessment revealed an extensive left ventricular (LV) chamber dilatation accompanied by elevated cardiomyopathy (CM) and fibrosis in the KO hearts post-TAC. In a gain-of-function model, NRK-2 overexpressing in AC16 cardiomyocytes displayed significantly attenuated fetal genes ANP and BNP expression. Consistently, NRK-2 overexpression attenuated angiotensin II (Ang II)-induced cardiomyocyte death. Mechanistically, we identified NRK-2 as a regulator of c-jun N-terminal kinase (JNK) MAP kinase and mitochondrial function where NRK-2 overexpression in human cardiomyocytes markedly suppressed the Ang II-induced JNK activation and mitochondrial depolarization. Thus, our results demonstrate that NRK-2 plays protective roles in pressure overload (PO)-induced dilatative cardiac remodeling and, genetic ablation exacerbates dilated cardiomyopathy (DCM), interstitial collagen deposition, and cardiac dysfunction post-TAC due, in part, to increased JNK activation and mitochondrial dysfunction.<\/jats:p>","DOI":"10.1042\/cs20210964","type":"journal-article","created":{"date-parts":[[2022,1,20]],"date-time":"2022-01-20T05:44:52Z","timestamp":1642657492000},"page":"181-196","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Nicotinamide riboside kinase-2 inhibits JNK pathway and limits dilated cardiomyopathy in mice with chronic pressure overload"],"prefix":"10.1042","volume":"136","author":[{"given":"Syeda\u00a0Kiran","family":"Shahzadi","sequence":"first","affiliation":[{"name":"Cardiovascular Research Group, Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hezlin","family":"Marzook","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Group, Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8485-7172","authenticated-orcid":false,"given":"Rizwan","family":"Qaisar","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Group, Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates"},{"name":"Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6530-6068","authenticated-orcid":false,"given":"Firdos","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Group, Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates"},{"name":"Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates"},{"name":"Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN 37240, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2022,1,28]]},"reference":[{"key":"2022012810363732100_B1","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1172\/JCI62862","article-title":"Genetic mutations and mechanisms in dilated cardiomyopathy","volume":"123","author":"McNally","year":"2013","journal-title":"J. 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