{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:12:55Z","timestamp":1760235175281,"version":"build-2065373602"},"reference-count":41,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2021,7,27]],"date-time":"2021-07-27T00:00:00Z","timestamp":1627344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01 HL089405","R01 HL115265"],"award-info":[{"award-number":["R01 HL089405","R01 HL115265"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Regulated\/activated protein kinase (PRAK) plays a crucial role in modulating biological function. However, the role of PRAK in mediating cardiac dysfunction and metabolic disorders remains unclear. We examined the effects of deletion of PRAK on modulating cardiac function and insulin resistance in mice exposed to a high-fat diet (HFD). Wild-type and PRAK\u2212\/\u2212 mice at 8 weeks old were exposed to either chow food or HFD for a consecutive 16 weeks. Glucose tolerance tests and insulin tolerance tests were employed to assess insulin resistance. Echocardiography was employed to assess myocardial function. Western blot was used to determine the molecular signaling involved in phosphorylation of IRS-1, AMPK\u03b1, ERK-44\/42, and irisin. Real time-PCR was used to assess the hypertrophic genes of the myocardium. Histological analysis was employed to assess the hypertrophic response, interstitial myocardial fibrosis, and apoptosis in the heart. Western blot was employed to determine cellular signaling pathway. HFD-induced metabolic stress is indicated by glucose intolerance and insulin intolerance. PRAK knockout aggravated insulin resistance, as indicated by glucose intolerance and insulin intolerance testing as compared with wild-type littermates. As compared with wild-type mice, hyperglycemia and hypercholesterolemia were manifested in PRAK-knockout mice following high-fat diet intervention. High-fat diet intervention displayed a decline in fractional shortening and ejection fraction. However, deletion of PRAK exacerbated the decline in cardiac function as compared with wild-type mice following HFD treatment. In addition, PRAK knockout mice enhanced the expression of myocardial hypertrophic genes including ANP, BNP, and \u03b2MHC in HFD treatment, which was also associated with an increase in cardiomyocyte size and interstitial fibrosis. Western blot indicated that deletion of PRAK induces decreases in phosphorylation of IRS-1, AMPK\u03b1, and ERK44\/42 as compared with wild-type controls. Our finding indicates that deletion of PRAK promoted myocardial dysfunction, cardiac remodeling, and metabolic disorders in response to HFD.<\/jats:p>","DOI":"10.3390\/ijms22157995","type":"journal-article","created":{"date-parts":[[2021,7,27]],"date-time":"2021-07-27T03:53:53Z","timestamp":1627358033000},"page":"7995","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The Essential Role of PRAK in Preserving Cardiac Function and Insulin Resistance in High-Fat Diet-Induced Diabetes"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6931-3337","authenticated-orcid":false,"given":"Jianfeng","family":"Du","sequence":"first","affiliation":[{"name":"Department of Surgery, Roger Williams Medical Center, Boston University School of Medicine, Providence, RI 02908, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu Tina","family":"Zhao","sequence":"additional","affiliation":[{"name":"University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Surgery, Roger Williams Medical Center, Boston University School of Medicine, Providence, RI 02908, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ling X.","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Surgery, Roger Williams Medical Center, Boston University School of Medicine, Providence, RI 02908, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gangjian","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9719-4187","authenticated-orcid":false,"given":"Shougang","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Rhode Island Hospital, Alpert Brown Medical School, Brown University, Providence, RI 02903, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1039-4384","authenticated-orcid":false,"given":"Marshall","family":"Kadin","sequence":"additional","affiliation":[{"name":"Department of Plastic Surgery, Rhode Island Hospital, Brown University, Providence, RI 02903, USA"},{"name":"Department of Pathology, Rhode Island Hospital, Alpert Brown Medical School, Brown University, Providence, RI 02903, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Y. Eugene","family":"Chin","sequence":"additional","affiliation":[{"name":"Institute of Health Sciences, Chinese Academy of Sciences-Jiaotong University School of Medicine, Shanghai 200031, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul Y.","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Plastic Surgery, Rhode Island Hospital, Brown University, Providence, RI 02903, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ting C.","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Surgery, Roger Williams Medical Center, Boston University School of Medicine, Providence, RI 02908, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3067","DOI":"10.1007\/s11033-009-9879-6","article-title":"Inhibition of MAPK signaling by eNOS gene transfer improves ventricular remodeling after myocardial infarction through reduction of inflammation","volume":"37","author":"Chen","year":"2010","journal-title":"Mol. 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