{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:41:17Z","timestamp":1760146877607,"version":"build-2065373602"},"reference-count":38,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2024,12,29]],"date-time":"2024-12-29T00:00:00Z","timestamp":1735430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81370284"],"award-info":[{"award-number":["81370284"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Irbesartan improves ventricular remodeling (VR) following myocardial infarction (MI). This study investigates whether irbesartan attenuates VR by reducing aldosterone production in the heart and its underlying mechanisms. MI was induced in male Sprague\u2013Dawley rats through coronary artery ligation. The MI rats were randomly assigned to two groups: one received a vehicle, and the other received 100 mg\/kg\/day of irbesartan for 5 weeks. Cardiac function and myocardial fibrosis were assessed using echocardiography and Masson\u2019s trichrome staining, respectively. The impact of angiotensin II (Ang II) stimulation on cardiac microvascular endothelial cells (CMECs) from commercial sources was determined using ELISA, real-time PCR, and Western blotting. Irbesartan reduced left ventricular mass index, collagen composition, and aldosterone levels while enhancing cardiac function in MI rats. In vitro, Ang II time-dependently stimulated aldosterone secretion and CYP11B2 mRNA expression in CMECs (p &lt; 0.05). Additionally, Ang II significantly upregulated p-CREB protein levels. However, these effects were abrogated by irbesartan and partially attenuated by CaMK inhibitor KN93 (p &lt; 0.05). In conclusion, our study demonstrated that improvement in VR by irbesartan coincided with reduced CREB phosphorylation in CMECs and reduced aldosterone synthesis in the non-infarcted tissue. These effects may be mediated by blocking the AT1 receptor.<\/jats:p>","DOI":"10.3390\/ijms26010198","type":"journal-article","created":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T07:34:19Z","timestamp":1735630459000},"page":"198","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Irbesartan May Ameliorate Ventricular Remodeling by Inhibiting CREB-Mediated Cardiac Aldosterone Synthesis in Rats with Myocardial Infarction"],"prefix":"10.3390","volume":"26","author":[{"given":"Jie","family":"Li","sequence":"first","affiliation":[{"name":"Department of Cardiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510800, China"},{"name":"Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510800, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9126-4117","authenticated-orcid":false,"given":"Guihua","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510800, China"},{"name":"Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510800, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5271-9912","authenticated-orcid":false,"given":"Haiwei","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510800, China"},{"name":"Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510800, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4478-0067","authenticated-orcid":false,"given":"Xiuren","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510800, China"},{"name":"Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510800, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuansheng","family":"Zhai","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510800, China"},{"name":"Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou 510800, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1001\/jama.292.3.344","article-title":"Trends in heart failure incidence and survival in a community-based population","volume":"292","author":"Roger","year":"2004","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e263","DOI":"10.1016\/j.jacc.2021.12.012","article-title":"2022 AHA\/ACC\/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology\/American Heart Association Joint Committee on Clinical Practice Guidelines","volume":"79","author":"Heidenreich","year":"2022","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Komai, K., Kawasaki, N.K., Higa, J.K., and Matsui, T. (2022). The Role of Ferroptosis in Adverse Left Ventricular Remodeling Following Acute Myocardial Infarction. Cells, 11.","DOI":"10.3390\/cells11091399"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2549","DOI":"10.1093\/eurheartj\/ehac223","article-title":"Left ventricular remodelling post-myocardial infarction: Pathophysiology, imaging, and novel therapies","volume":"43","author":"Frantz","year":"2022","journal-title":"Eur. Heart J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2219","DOI":"10.1016\/j.jacc.2020.03.020","article-title":"Extracellular Matrix in Ischemic Heart Disease, Part 4\/4: JACC Focus Seminar","volume":"75","author":"Frangogiannis","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.ejphar.2008.03.006","article-title":"Fluvastatin decreases cardiac fibrosis possibly through regulation of TGF-\u03b21\/Smad 7 expression in the spontaneously hypertensive rats","volume":"587","author":"Zhai","year":"2008","journal-title":"Eur. J. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1899","DOI":"10.1161\/HYPERTENSIONAHA.122.17964","article-title":"Aldosterone as a Mediator of Cardiovascular Damage","volume":"79","author":"Buffolo","year":"2022","journal-title":"Hypertension"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1186\/s13020-020-00345-7","article-title":"The protective effects of liguzinediol on congestive heart failure induced by myocardial infarction and its relative mechanism","volume":"15","author":"Chen","year":"2020","journal-title":"Chin. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1056\/NEJMoa2213169","article-title":"Phase 2 Trial of Baxdrostat for Treatment-Resistant Hypertension","volume":"388","author":"Freeman","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4883","DOI":"10.1074\/jbc.273.9.4883","article-title":"Myocardial production of aldosterone and corticosterone in the rat. Physiological regulation","volume":"273","author":"Silvestre","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Zhai, Y.S., Li, J., Peng, L., Lu, G., and Gao, X. (2022). Phosphorylation of CaMK and CREB-Mediated Cardiac Aldosterone Synthesis Induced by Arginine Vasopressin in Rats with Myocardial Infarction. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232315061"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1210\/me.2003-0005","article-title":"The orphan nuclear receptors NURR1 and NGFIB regulate adrenal aldosterone production","volume":"18","author":"Bassett","year":"2004","journal-title":"Mol. Endocrinol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Akhtar, H., Al Sudani, H., Hussein, M., Farhan, M.U.N., and Elkholy, K. (2022). Effects of Renin-Angiotensin-Aldosterone System Inhibition on Left Ventricular Hypertrophy, Diastolic Function, and Functional Status in Patients with Hypertrophic Cardiomyopathy: A Systematic Review. Cureus, 14.","DOI":"10.7759\/cureus.26642"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.kisu.2021.11.001","article-title":"Mineralocorticoid receptor activation and antagonism in cardiovascular disease: Cellular and molecular mechanisms","volume":"12","author":"Bauersachs","year":"2022","journal-title":"Kidney Int. Suppl."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1007\/s10557-012-6392-2","article-title":"ARB and cardioprotection","volume":"27","author":"Akazawa","year":"2013","journal-title":"Cardiovasc. Drugs Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.1056\/NEJMoa010713","article-title":"A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure","volume":"345","author":"Cohn","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1177\/1074248419869618","article-title":"Late Versus Early Myocardial Remodeling After Acute Myocardial Infarction: A Comparative Review on Mechanistic Insights and Clinical Implications","volume":"25","author":"Yalta","year":"2020","journal-title":"J. Cardiovasc. Pharmacol. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Berezin, A.E., and Berezin, A.A. (2020). Adverse Cardiac Remodelling after Acute Myocardial Infarction: Old and New Biomarkers. Dis. Markers, 2020.","DOI":"10.1155\/2020\/1215802"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"108658","DOI":"10.1016\/j.intimp.2022.108658","article-title":"The selective STING inhibitor H-151 preserves myocardial function and ameliorates cardiac fibrosis in murine myocardial infarction","volume":"107","author":"Hu","year":"2022","journal-title":"Int. Immunopharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1002\/ehf2.12249","article-title":"The impact of a dose of the angiotensin receptor blocker valsartan on post-myocardial infarction ventricular remodelling","volume":"5","author":"Park","year":"2018","journal-title":"ESC Heart Fail."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1536\/ihj.48.715","article-title":"A new therapeutic strategy for hypertrophic nonobstructive cardiomyopathy in humans. A randomized and prospective study with an Angiotensin II receptor blocker","volume":"48","author":"Yamazaki","year":"2007","journal-title":"Int. Heart J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1016\/j.amjcard.2010.11.033","article-title":"Effect of left ventricular reverse remodeling on long-term prognosis after therapy with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers and \u03b2 blockers in patients with idiopathic dilated cardiomyopathy","volume":"107","author":"Hoshikawa","year":"2011","journal-title":"Am. J. Cardiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"877","DOI":"10.2169\/internalmedicine.48.1948","article-title":"Effects of enalapril and losartan in left ventricular remodeling after acute myocardial infarction: A possible mechanism of prevention of cardiac events by angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in high-risk myocardial infarction","volume":"48","author":"Tani","year":"2009","journal-title":"Intern. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.cardiores.2005.03.001","article-title":"Additive amelioration of left ventricular remodeling and molecular alterations by combined aldosterone and angiotensin receptor blockade after myocardial infarction","volume":"67","author":"Fraccarollo","year":"2005","journal-title":"Cardiovasc. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1161\/01.CIR.0000057794.29667.08","article-title":"Inhibitory effect of natriuretic peptides on aldosterone synthase gene expression in cultured neonatal rat cardiocytes","volume":"107","author":"Ito","year":"2003","journal-title":"Circulation"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"24316","DOI":"10.1016\/S0021-9258(19)51084-5","article-title":"Vascular aldosterone. Biosynthesis and a link to angiotensin II-induced hypertrophy of vascular smooth muscle cells","volume":"269","author":"Hatakeyama","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Zhuo, X., Bai, K., Wang, Y., Liu, P., Xi, W., She, J., and Liu, J. (2021). Long-chain noncoding RNA-GAS5\/hsa-miR-138-5p attenuates high glucose-induced cardiomyocyte damage by targeting CYP11B2. Biosci. Rep., 41.","DOI":"10.1042\/BSR20202232"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2530","DOI":"10.1161\/CIRCULATIONAHA.118.034621","article-title":"Inflammation and NLRP3 Inflammasome Activation Initiated in Response to Pressure Overload by Ca2+\/Calmodulin-Dependent Protein Kinase II delta Signaling in Cardiomyocytes Are Essential for Adverse Cardiac Remodeling","volume":"138","author":"Suetomi","year":"2018","journal-title":"Circulation"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Chen, T., Kong, B., Shuai, W., Gong, Y., Zhang, J., and Huang, H. (2023). Vericiguat alleviates ventricular remodeling and arrhythmias in mouse models of myocardial infarction via CaMKII signaling. Life Sci., 334.","DOI":"10.1016\/j.lfs.2023.122184"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1161\/CIRCRESAHA.121.319478","article-title":"Targeting CaMKII-delta9 Ameliorates Cardiac Ischemia\/Reperfusion Injury by Inhibiting Myocardial Inflammation","volume":"130","author":"Yao","year":"2022","journal-title":"Circ. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3496","DOI":"10.1002\/jcp.25810","article-title":"STIM-1 and ORAI-1 channel mediate angiotensin-II-induced expression of Egr-1 in vascular smooth muscle cells","volume":"232","author":"Tan","year":"2017","journal-title":"J. Cell. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1210\/en.2009-0977","article-title":"Regulation of aldosterone synthase by activator transcription factor\/cAMP response element-binding protein family members","volume":"151","author":"Nogueira","year":"2010","journal-title":"Endocrinology"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Takeda, Y., Demura, M., Kometani, M., Karashima, S., Yoneda, T., and Takeda, Y. (2023). Molecular and Epigenetic Control of Aldosterone Synthase, CYP11B2 and 11-Hydroxylase, CYP11B1. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24065782"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1093\/oxfordjournals.jbchem.a123303","article-title":"Novel cAMP regulatory elements in the promoter region of bovine P-450(11\u03b2) gene","volume":"108","author":"Honda","year":"1990","journal-title":"J. Biochem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"9130","DOI":"10.1016\/S0021-9258(18)52987-2","article-title":"Isolation and characterization of rat CYP11B genes involved in late steps of mineralo- and glucocorticoid syntheses","volume":"268","author":"Mukai","year":"1993","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/S0303-7207(99)00051-9","article-title":"Adrenal zonation: Clues from 11\u03b2-hydroxylase and aldosterone synthase","volume":"151","author":"Rainey","year":"1999","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1046\/j.1523-1755.2000.00973.x","article-title":"Cardiac aldosterone production and ventricular remodeling","volume":"57","author":"Delcayre","year":"2000","journal-title":"Kidney Int."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/j.jacc.2010.08.635","article-title":"Adrenal beta-arrestin 1 inhibition in vivo attenuates post-myocardial infarction progression to heart failure and adverse remodeling via reduction of circulating aldosterone levels","volume":"57","author":"Lymperopoulos","year":"2011","journal-title":"J. Am. Coll. Cardiol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/1\/198\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:56:01Z","timestamp":1760115361000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/1\/198"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,29]]},"references-count":38,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1]]}},"alternative-id":["ijms26010198"],"URL":"https:\/\/doi.org\/10.3390\/ijms26010198","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2024,12,29]]}}}