{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T11:55:20Z","timestamp":1792065320844,"version":"4.4.0"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,1,10]],"date-time":"2024-01-10T00:00:00Z","timestamp":1704844800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Vascular endothelial injury is a contributing factor to the development of atherosclerosis and the resulting cardiovascular diseases. One particular factor involved in endothelial cell apoptosis and atherosclerosis is palmitic acid (PA), which is a long-chain saturated fatty acid. In addition, transient receptor potential melastatin 4 (TRPM4), a non-selective cation channel, plays a significant role in endothelial dysfunction caused by various factors related to cardiovascular diseases. Despite this, the specific role and mechanisms of TRPM4 in atherosclerosis have not been fully understood.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> The protein and mRNA expressions of TRPM4, apoptosis - and inflammation-related factors were measured after PA treatment. The effect of TRPM4 knockout on the protein and mRNA expression of apoptosis and inflammation-related factors was detected. The changes of intracellular Ca<jats:sup>2+<\/jats:sup>, mitochondrial membrane potential, and reactive oxygen species were detected by Fluo-4 AM, JC-1, and DCFH-DA probes, respectively. To confirm the binding of miR-133a-3p to TRPM4, a dual luciferase reporter gene assay was conducted. Finally, the effects of miR-133a-3p and TRPM4 on intracellular Ca<jats:sup>2+<\/jats:sup>, mitochondrial membrane potential, and reactive oxygen species were examined.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> Following PA treatment, the expression of TRPM4 increases, leading to calcium overload in endothelial cells. This calcium influx causes the assemblage of Bcl-2, resulting in the opening of mitochondrial calcium channels and mitochondrial damage, ultimately triggering apoptosis. Throughout this process, the mRNA and protein levels of IL-1\u03b2, ICAM-1, and VCAM1 significantly increase. Database screenings and luciferase assays have shown that miR-133a-3p preferentially binds to the 3\u2032UTR region of TRPM4 mRNA, suppressing TRPM4 expression. During PA-induced endothelial injury, miR-133a-3p is significantly decreased, but overexpression of miR-133a-3p can attenuate the progression of endothelial injury. On the other hand, overexpression of TRPM4 counteracts the aforementioned changes.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> TRPM4 participates in vascular endothelial injury caused by PA. Therefore, targeting TRPM4 or miR-133a-3p may offer a novel pharmacological approach to preventing endothelial injury.<\/jats:p>","DOI":"10.3389\/fphar.2023.1340247","type":"journal-article","created":{"date-parts":[[2024,1,10]],"date-time":"2024-01-10T04:47:21Z","timestamp":1704862041000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["miR-133a-3p\/TRPM4 axis improves palmitic acid induced vascular endothelial injury"],"prefix":"10.3389","volume":"14","author":[{"given":"Yadong","family":"Xue","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Tong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuyao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haijun","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongzhao","family":"Lv","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingzhao","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxuan","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuyang","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongzhen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Huo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Ban","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,1,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1186\/s12872-022-02711-9","article-title":"Identification of a circulating microRNAs biomarker panel for non-invasive diagnosis of coronary artery disease: case-control study","volume":"22","author":"Abdallah","year":"2022","journal-title":"BMC Cardiovasc. Disord."},{"key":"B2","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1016\/j.bcp.2012.06.021","article-title":"TRPM4 channels in the cardiovascular system: physiology, pathophysiology, and pharmacology","volume":"84","author":"Abriel","year":"2012","journal-title":"Biochem. Pharmacol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"6615038","DOI":"10.1155\/2020\/6615038","article-title":"Inherited cardiac arrhythmia syndromes: focus on molecular mechanisms underlying TRPM4 channelopathies","volume":"2020","author":"Amarouch","year":"2020","journal-title":"Cardiovasc. Ther."},{"key":"B4","doi-asserted-by":"publisher","first-page":"2425","DOI":"10.3892\/etm.2019.7269","article-title":"Palmitic acid-induced autophagy increases reactive oxygen species via the Ca\n            2+\n            \/PKC\u03b1\/NOX4 pathway and impairs endothelial function in human umbilical vein endothelial cells","volume":"17","author":"Chen","year":"2019","journal-title":"Exp. Ther. Med."},{"key":"B5","doi-asserted-by":"publisher","first-page":"e13322","DOI":"10.1111\/apha.13322","article-title":"MicroRNA-133 suppresses ZFHX3-dependent atrial remodelling and arrhythmia","volume":"227","author":"Cheng","year":"2019","journal-title":"Acta Physiol. (Oxf)"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1610","DOI":"10.1001\/archinte.167.15.1610","article-title":"A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: results from the Women's Antioxidant Cardiovascular Study","volume":"167","author":"Cook","year":"2007","journal-title":"Archives Intern. Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1591","DOI":"10.1111\/bph.13517","article-title":"Targeting vascular (endothelial) dysfunction","volume":"174","author":"Daiber","year":"2017","journal-title":"Br. J. Pharmacol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1016\/j.jid.2022.08.034","article-title":"miRNA-203b-3p induces acute and chronic pruritus through 5-HTR2B and TRPV4","volume":"143","author":"De Logu","year":"2023","journal-title":"J. Invest. Dermatol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"40","DOI":"10.3390\/ph15010040","article-title":"Pharmacological modulation and (Patho)Physiological roles of TRPM4 channel-Part 2: TRPM4 in health and disease","volume":"15","author":"Dienes","year":"2021","journal-title":"Pharm. (Basel, Switz."},{"key":"B10","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/s1734-1140(09)70014-3","article-title":"Mitochondria and vascular pathology","volume":"61","author":"Di Lisa","year":"2009","journal-title":"Pharmacol. Rep. P. R."},{"key":"B11","doi-asserted-by":"publisher","first-page":"3720","DOI":"10.1182\/blood-2010-07-273417","article-title":"Interleukin-1 in the pathogenesis and treatment of inflammatory diseases","volume":"117","author":"Dinarello","year":"2011","journal-title":"Blood"},{"key":"B12","doi-asserted-by":"publisher","first-page":"101015","DOI":"10.1016\/j.jbc.2021.101015","article-title":"TRPM4 links calcium signaling to membrane potential in pancreatic acinar cells","volume":"297","author":"Diszh\u00e1zi","year":"2021","journal-title":"J. Biol. Chem."},{"key":"B13","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1080\/13813455.2018.1441315","article-title":"Natural products for controlling hyperlipidemia: review","volume":"125","author":"El-Tantawy","year":"2019","journal-title":"Archives Physiology Biochem."},{"key":"B14","doi-asserted-by":"publisher","first-page":"83","DOI":"10.3389\/fcvm.2019.00083","article-title":"TRP channels mediated pathological Ca2+-handling and spontaneous ectopy","volume":"6","author":"Ezeani","year":"2019","journal-title":"Front. Cardiovasc. Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1111\/j.1749-6632.2003.tb07469.x","article-title":"Mitochondrial mechanisms of neural cell death and neuroprotective interventions in Parkinson's disease","volume":"991","author":"Fiskum","year":"2003","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"B16","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1016\/j.atherosclerosis.2013.11.029","article-title":"MicroRNA-133a regulates insulin-like growth factor-1 receptor expression and vascular smooth muscle cell proliferation in murine atherosclerosis","volume":"232","author":"Gao","year":"2014","journal-title":"Atherosclerosis"},{"key":"B17","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1038\/sj.cdd.4400786","article-title":"Early stages of p53-induced apoptosis are reversible","volume":"8","author":"Geske","year":"2001","journal-title":"Cell Death Differ."},{"key":"B18","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1093\/cvr\/cvv213","article-title":"TRPM4 in cardiac electrical activity","volume":"108","author":"Guinamard","year":"2015","journal-title":"Cardiovasc. Res."},{"key":"B19","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1152\/physiol.00004.2010","article-title":"Physiological roles of the TRPM4 channel extracted from background currents","volume":"25","author":"Guinamard","year":"2010","journal-title":"Physiol. (Bethesda, Md.)"},{"key":"B20","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1161\/CIRCRESAHA.115.307611","article-title":"Epidemiology of atherosclerosis and the potential to reduce the global burden of atherothrombotic disease","volume":"118","author":"Herrington","year":"2016","journal-title":"Circulation Res."},{"key":"B21","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1038\/s41569-018-0145-2","article-title":"Transient receptor potential channels in cardiac health and disease","volume":"16","author":"Hof","year":"2019","journal-title":"Nat. Rev. Cardiol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1002\/biof.1395","article-title":"Dihydromyricetin inhibits NLRP3 inflammasome-dependent pyroptosis by activating the Nrf2 signaling pathway in vascular endothelial cells","volume":"44","author":"Hu","year":"2018","journal-title":"BioFactors Oxf. Engl."},{"key":"B23","doi-asserted-by":"publisher","first-page":"101610","DOI":"10.1016\/j.arr.2022.101610","article-title":"Noncoding RNAs in age-related cardiovascular diseases","volume":"77","author":"Jusic","year":"2022","journal-title":"Ageing Res. Rev."},{"key":"B24","doi-asserted-by":"publisher","first-page":"910","DOI":"10.1016\/j.clnu.2019.03.033","article-title":"Differential circulating and visceral fat microRNA expression of non-obese and obese subjects","volume":"39","author":"Kim","year":"2020","journal-title":"Clin. Nutr. Edinb. Scotl."},{"key":"B25","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/s1734-1140(09)70004-0","article-title":"ICAM-1 signaling in endothelial cells","volume":"61","author":"Lawson","year":"2009","journal-title":"Pharmacol. Rep. P. R."},{"key":"B26","doi-asserted-by":"publisher","first-page":"903","DOI":"10.3389\/fphar.2018.00903","article-title":"miR-133: a suppressor of cardiac remodeling?","volume":"9","author":"Li","year":"2018","journal-title":"Front. Pharmacol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1038\/s41572-019-0106-z","volume":"5","author":"Libby","year":"2019","journal-title":"Atheroscler."},{"key":"B28","doi-asserted-by":"publisher","first-page":"e922032","DOI":"10.12659\/MSM.922032","article-title":"Overexpression of MicroRNA-133a inhibits apoptosis and autophagy in a cell model of Parkinson's disease by downregulating ras-related C3 botulinum toxin substrate 1 (RAC1)","volume":"26","author":"Lu","year":"2020","journal-title":"Med. Sci. Monit."},{"key":"B29","doi-asserted-by":"publisher","first-page":"e159","DOI":"10.1161\/ATVBAHA.118.310227","article-title":"Impact of miRNA in atherosclerosis","volume":"38","author":"Lu","year":"2018","journal-title":"Arteriosclerosis, Thrombosis, Vasc. Biol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"301","DOI":"10.3390\/biom9080301","article-title":"Antioxidants and atherosclerosis: mechanistic aspects","volume":"9","author":"Malekmohammad","year":"2019","journal-title":"Biomolecules"},{"key":"B31","doi-asserted-by":"publisher","first-page":"130","DOI":"10.2174\/1871527320666210119095626","article-title":"ATP-Sensitive potassium channel subunits in neuroinflammation: novel drug targets in neurodegenerative disorders","volume":"21","author":"Maqoud","year":"2022","journal-title":"CNS Neurological Disord. Drug Targets"},{"key":"B32","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1152\/physrev.00012.2005","article-title":"Signaling mechanisms regulating endothelial permeability","volume":"86","author":"Mehta","year":"2006","journal-title":"Physiol. Rev."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1926","DOI":"10.1038\/mt.2016.160","article-title":"GDF11 protects against endothelial injury and reduces atherosclerotic lesion formation in apolipoprotein E-null mice","volume":"24","author":"Mei","year":"2016","journal-title":"Mol. Ther. J. Am. Soc. Gene Ther."},{"key":"B34","doi-asserted-by":"publisher","first-page":"101012","DOI":"10.1016\/j.cpcardiol.2021.101012","article-title":"Viewpoints on the role of transient receptor potential melastatin channels in cardiovascular system and disease: a systematic review","volume":"48","author":"Mirbod","year":"2023","journal-title":"Curr. Problems Cardiol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1093\/cvr\/cvw174","article-title":"Identifying circulating microRNAs as biomarkers of cardiovascular disease: a systematic review","volume":"111","author":"Navickas","year":"2016","journal-title":"Cardiovasc. Res."},{"key":"B36","doi-asserted-by":"publisher","first-page":"73","DOI":"10.3389\/fcvm.2017.00073","article-title":"MiRroring the multiple potentials of MicroRNAs in acute myocardial infarction","volume":"4","author":"Paiva","year":"2017","journal-title":"Front. Cardiovasc. Med."},{"key":"B37","doi-asserted-by":"publisher","first-page":"2986","DOI":"10.1002\/oby.23899","article-title":"Visceral adipocyte size links obesity with dysmetabolism more than fibrosis, and both can be estimated by circulating miRNAs","volume":"31","author":"Pincu","year":"2023","journal-title":"Obes. (Silver Spring)"},{"key":"B38","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1007\/s11883-021-00938-z","article-title":"Novel RNAi-based therapies for atherosclerosis","volume":"23","author":"Ruotsalainen","year":"2021","journal-title":"Curr. Atheroscler. Rep."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1483","DOI":"10.3390\/ijerph18041483","article-title":"Mir-1, miR-122, miR-132, and miR-133 are related to subclinical aortic atherosclerosis associated with metabolic syndrome","volume":"18","author":"\u0160atrauskien\u0117","year":"2021","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"B40","doi-asserted-by":"publisher","first-page":"2123","DOI":"10.1001\/jama.2008.600","article-title":"Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial","volume":"300","author":"Sesso","year":"2008","journal-title":"JAMA"},{"key":"B41","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1142\/S0192415X19500058","article-title":"Clinopodium chinense attenuates palmitic acid-induced vascular endothelial inflammation and insulin resistance through TLR4-mediated NF- B and MAPK pathways","volume":"47","author":"Shi","year":"2019","journal-title":"Am. J. Chin. Med."},{"key":"B42","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1002\/iub.1130","article-title":"What is the nature of the mitochondrial permeability transition pore and what is it not?","volume":"65","author":"Siemen","year":"2013","journal-title":"IUBMB Life"},{"key":"B43","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1007\/s00441-008-0678-5","article-title":"Vascular endothelium in atherosclerosis","volume":"335","author":"Sima","year":"2009","journal-title":"Cell Tissue Res."},{"key":"B44","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1007\/3-540-32967-6_2","article-title":"Functional ultrastructure of the vascular endothelium: changes in various pathologies","author":"Simionescu","year":"2006","journal-title":"Handb. Exp. Pharmacol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1016\/j.tips.2021.11.001","article-title":"Physiological and pharmacological modulation of BAX","volume":"43","author":"Spitz","year":"2022","journal-title":"Trends Pharmacol. Sci."},{"key":"B46","doi-asserted-by":"publisher","first-page":"e0120707","DOI":"10.1371\/journal.pone.0120707","article-title":"G-CSF protects human brain vascular endothelial cells injury induced by high glucose, free fatty acids and hypoxia through MAPK and Akt signaling","volume":"10","author":"Su","year":"2015","journal-title":"PloS One"},{"key":"B47","doi-asserted-by":"publisher","first-page":"166170","DOI":"10.1016\/j.bbadis.2021.166170","article-title":"VCAM-1 as a predictor biomarker in cardiovascular disease","volume":"1867","author":"Troncoso","year":"2021","journal-title":"Biochimica Biophysica Acta. Mol. Basis Dis."},{"key":"B48","doi-asserted-by":"publisher","first-page":"62","DOI":"10.3390\/cells7060062","article-title":"Role of the TRPM4 channel in cardiovascular physiology and pathophysiology","volume":"7","author":"Wang","year":"2018","journal-title":"Cells"},{"key":"B49","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1253\/circj.cj-08-1153","article-title":"The pathological role of transient receptor potential channels in heart disease","volume":"73","author":"Watanabe","year":"2009","journal-title":"Circulation J. Official J. Jpn. Circulation Soc."},{"key":"B50","doi-asserted-by":"publisher","first-page":"112404","DOI":"10.1016\/j.jep.2019.112404","article-title":"Astragaloside IV inhibits cardiac fibrosis via miR-135a-TRPM7-TGF-\u03b2\/Smads pathway","volume":"249","author":"Wei","year":"2020","journal-title":"J. Ethnopharmacol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"924","DOI":"10.1124\/pharmrev.120.000096","article-title":"Endothelial dysfunction in atherosclerotic cardiovascular diseases and beyond: from mechanism to pharmacotherapies","volume":"73","author":"Xu","year":"2021","journal-title":"Pharmacol. Rev."},{"key":"B52","doi-asserted-by":"publisher","first-page":"1511","DOI":"10.3892\/ijmm.2017.3152","article-title":"MicroRNA-135a is involved in podocyte injury in a transient receptor potential channel 1-dependent manner","volume":"40","author":"Yang","year":"2017","journal-title":"Int. J. Mol. Med."},{"key":"B53","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1161\/01.RES.0000187473.85419.3e","article-title":"Recent developments in vascular endothelial cell transient receptor potential channels","volume":"97","author":"Yao","year":"2005","journal-title":"Circulation Res."},{"key":"B54","doi-asserted-by":"publisher","first-page":"534","DOI":"10.1152\/physiolgenomics.00130.2010","article-title":"The role of microRNA in modulating myocardial ischemia-reperfusion injury","volume":"43","author":"Ye","year":"2011","journal-title":"Physiol. Genomics"},{"key":"B55","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.toxlet.2019.04.035","article-title":"Transient receptor potential melastatin 4 contributes to early-stage endothelial injury induced by arsenic trioxide","volume":"312","author":"Yu","year":"2019","journal-title":"Toxicol. Lett."},{"key":"B56","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1016\/j.redox.2018.09.025","article-title":"New insights into oxidative stress and inflammation during diabetes mellitus-accelerated atherosclerosis","volume":"20","author":"Yuan","year":"2019","journal-title":"Redox Biol."}],"updated-by":[{"DOI":"10.3389\/fphar.2026.1960435","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T00:00:00Z","timestamp":1792022400000}}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1340247\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,10]],"date-time":"2024-01-10T04:47:23Z","timestamp":1704862043000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1340247\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,10]]},"references-count":56,"alternative-id":["10.3389\/fphar.2023.1340247"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2023.1340247","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,10]]},"article-number":"1340247"}}