{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:48:44Z","timestamp":1787028524434,"version":"build-2736575974"},"reference-count":50,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2023,9,26]],"date-time":"2023-09-26T00:00:00Z","timestamp":1695686400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["81873470"],"award-info":[{"award-number":["81873470"]}]},{"name":"National Natural Science Foundation of China","award":["82070418"],"award-info":[{"award-number":["82070418"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Necroptosis is a newly discovered mechanism of cell death, and its key regulatory role is attributed to the interaction of receptor-interacting protein kinases (RIPKs) RIPK1 and RIPK3. Ca2+\/calmodulin-dependent protein kinase (CaMKII) is a newly discovered RIPK3 substrate, and its alternative splicing plays a fundamental role in cardiovascular diseases. In the present study, we aimed to explore the role and mechanism of necroptosis and alternative splicing of CaMKII\u03b4 in myocardial hypertrophy. Transverse aortic constriction (TAC) was performed on wild-type and knockout mice to establish the model of myocardial hypertrophy. After 3 weeks, echocardiography, cardiac index, cross-sectional area of myocardial cells, hypertrophic gene expression, myocardial damage, and fibers were assessed. Moreover, we detected the levels of inflammatory factors (IL-6 and TNF-\u03b1) and examined the expressions of necroptosis-related proteins RIPK3, RIPK1, and phosphorylated MLKL. Meanwhile, we tested the expression levels of splicing factors ASF\/SF2 and SC-35 in an attempt to explore CaMKII \u03b4. The relationship between variable splicing disorder and the expression levels of splicing factors ASF\/SF2 and SC-35. Further, we also investigated CaMKII activation, oxidative stress, and mitochondrial ultrastructure. In addition, wild-type mice were administered with a recombinant adeno-associated virus (AAV) carrying RIPK3, followed by TAC surgery to construct a model of myocardial hypertrophy, and the above-mentioned indicators were tested after 3 weeks. The results showed that RIPK3 deficiency could alleviate cardiac dysfunction, myocardial injury, aggravation of necrosis, and CaMKII activation induced by TAC surgery in mice with myocardial hypertrophy. Tail vein injection of AAV could reverse cardiac dysfunction, myocardial damage, aggravation of necrosis, and CaMKII activation in mice with myocardial hypertrophy. These results proved that RIPK3 could be used as a molecular intervention target for the prevention and treatment of myocardial hypertrophy.<\/jats:p>","DOI":"10.3390\/ijms241914529","type":"journal-article","created":{"date-parts":[[2023,9,26]],"date-time":"2023-09-26T03:53:00Z","timestamp":1695700380000},"page":"14529","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["The Regulatory Effect of Receptor-Interacting Protein Kinase 3 on CaMKII\u03b4 in TAC-Induced Myocardial Hypertrophy"],"prefix":"10.3390","volume":"24","author":[{"given":"Jianan","family":"Qian","sequence":"first","affiliation":[{"name":"School of Pharmacy, Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Nantong University, Nantong 226001, China"},{"name":"School of Medicine, Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji","family":"Cao","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Nantong University, Nantong 226001, China"},{"name":"School of Medicine, Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangfan","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Nantong University, Nantong 226001, China"},{"name":"School of Medicine, Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1111\/j.1440-1681.2009.05243.x","article-title":"Downregulation of survival signalling pathways and increased apoptosis in the transition of pressure overload-induced cardiac hypertrophy to heart failure","volume":"36","author":"Li","year":"2009","journal-title":"Clin. 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