{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:02:18Z","timestamp":1760148138850,"version":"build-2065373602"},"reference-count":78,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,4,1]],"date-time":"2023-04-01T00:00:00Z","timestamp":1680307200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Heart, Lung, And Blood Institute of the National Institutes of Health","award":["R01HL162579","5I01BX004870-03"],"award-info":[{"award-number":["R01HL162579","5I01BX004870-03"]}]},{"name":"Miami VA Health System","award":["R01HL162579","5I01BX004870-03"],"award-info":[{"award-number":["R01HL162579","5I01BX004870-03"]}]},{"name":"Miami Heart Research Institute","award":["R01HL162579","5I01BX004870-03"],"award-info":[{"award-number":["R01HL162579","5I01BX004870-03"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cocaine abuse increases the risk of atherosclerotic cardiovascular disease (CVD) and causes acute coronary syndromes (ACS) and hypertension (HTN). Significant research has explored the role of the sympathetic nervous system mediating the cocaine effects on the cardiovascular (CV) system. However, the response of the sympathetic nervous system alone is insufficient to completely account for the CV consequences seen in cocaine users. In this study, we examined the role of microRNAs (miRNAs) in mediating the effect of cocaine on the CV system. MiRNAs regulate many important biological processes and have been associated with both response to cocaine and CV disease development. Multiple miRNAs have altered expression in the CV system (CVS) upon cocaine exposure. To understand the molecular mechanisms underlying the cocaine response in the CV system, we studied the role of miRNA-423-5p and its target Cacna2d2 in the regulation of intracellular calcium concentration and SMC contractility, a critical factor in the modulation of blood pressure (BP). We used in vivo models to evaluate BP and aortic stiffness. In vitro, cocaine treatment decreased miR-423-5p expression and increased Cacna2d2 expression, which led to elevated intracellular calcium concentrations and increased SMC contractility. Overexpression of miR-423-5p, silencing of its target Cacna2d2, and treatment with a calcium channel blocker reversed the elevated SMC contractility caused by cocaine. In contrast, suppression of miR-423-5p increased the intracellular calcium concentration and SMC contractibility. In vivo, smooth muscle-specific overexpression of miR-423-5p ameliorated the increase in BP and aortic stiffness associated with cocaine use. Thus, miR-423-5p regulates SMC contraction by modulating Cacna2d2 expression increasing intracellular calcium concentrations. Modulation of the miR-423-5p\u2014Cacna2d2\u2014Calcium transport pathway may represent a novel therapeutic strategy to improve cocaine-induced HTN and aortic stiffness.<\/jats:p>","DOI":"10.3390\/ijms24076584","type":"journal-article","created":{"date-parts":[[2023,4,3]],"date-time":"2023-04-03T03:08:31Z","timestamp":1680491311000},"page":"6584","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["MicroRNA-423-5p Mediates Cocaine-Induced Smooth Muscle Cell Contraction by Targeting Cacna2d2"],"prefix":"10.3390","volume":"24","author":[{"given":"Derek M.","family":"Dykxhoorn","sequence":"first","affiliation":[{"name":"Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL 33136, USA"},{"name":"Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33136, USA"},{"name":"John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1413-2901","authenticated-orcid":false,"given":"Huilan","family":"Wang","sequence":"additional","affiliation":[{"name":"Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Da Fonseca Ferreira","sequence":"additional","affiliation":[{"name":"Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA"},{"name":"Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7990-5870","authenticated-orcid":false,"given":"Jianqin","family":"Wei","sequence":"additional","affiliation":[{"name":"Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunming","family":"Dong","sequence":"additional","affiliation":[{"name":"Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA"},{"name":"Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA"},{"name":"Section of Cardiology, Miami VA Health Systems, Miami, FL 33136, USA"},{"name":"Biomedical Research Building, Suite 812, 1501 NW 10th Avenue, Miami, FL 33136, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1016\/j.amjmed.2016.12.003","article-title":"Hospital Admissions for Chest Pain Associated with Cocaine Use in the United States","volume":"130","author":"Singh","year":"2017","journal-title":"Am. 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