{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T03:08:46Z","timestamp":1784084926083,"version":"3.55.0"},"reference-count":39,"publisher":"Portland Press Ltd.","issue":"03","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,2,12]]},"abstract":"<jats:p>Dysregulated renin-angiotensin system (RAS) signaling contributes to elevated blood pressure (BP), inflammation, and organ damage in systemic arterial hypertension (HTN). We have demonstrated that hypertensive humans and rats exhibit higher expression of classic RAS components and lower expression of counterregulatory RAS components in the lungs compared with normotensive counterparts. Here, we investigated whether BP control could restore the balance between classic [angiotensin I-converting enzyme 2 (ACE)\/angiotensin II (Ang II)] and counterregulatory [angiotensin I-converting enzyme 2 (ACE2)\/Ang (1-7)] RAS, thereby mitigating lung inflammation. Male spontaneously hypertensive rats (SHRs) were treated with either losartan or amlodipine, both of which effectively reduced BP. These interventions up-regulated lung Ace2 and down-regulated Ace gene expression. Pulmonary membrane ACE2 abundance and activity were higher in losartan- and amlodipine-treated SHRs than in vehicle-treated SHRs, whereas ACE protein and function remained unchanged. Drug-treated SHRs exhibited lower levels of lung Ang II and higher levels of Ang (1-7) than vehicle-treated SHRs. Rebalancing the pulmonary RAS remarkably reduced macrophage number and down-regulated pro-inflammatory genes in SHR lungs, with lower expression of lung pro-inflammatory genes correlating with lower circulating levels of ACE2. Serum analysis in healthy and hypertensive individuals supported these findings, showing higher ACE2 levels in uncontrolled compared with controlled hypertension and normotension. Collectively, these findings suggest that high blood pressure may induce lung inflammation via an ACE\/ACE2 imbalance. BP control with either an RAS inhibitor or a calcium channel blocker rebalances RAS in SHR lungs and alleviates inflammation. Furthermore, this study provides a mechanistic link between inflammatory lung diseases (such as COVID-19) and hypertension as a major risk factor.<\/jats:p>","DOI":"10.1042\/cs20241155","type":"journal-article","created":{"date-parts":[[2025,2,13]],"date-time":"2025-02-13T08:23:11Z","timestamp":1739434991000},"page":"215-227","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Restoring lung renin-angiotensin system balance through blood pressure control"],"prefix":"10.1042","volume":"139","author":[{"given":"Gabriela Cat\u00e3o D.","family":"Braga","sequence":"first","affiliation":[{"name":"1Laborat\u00f3rio de Gen\u00e9tica e Cardiologia Molecular, Faculdade de Medicina, Instituto do Cora\u00e7\u00e3o (InCor), Hospital das Cl\u00ednicas HCFMUSP, Universidade de S\u00e3o Paulo, S\u00e3o Paulo, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joao Carlos","family":"Ribeiro-Silva","sequence":"additional","affiliation":[{"name":"2Department of Ophthalmology and Visual Sciences, State University of New York (SUNY) Upstate Medical University, Syracuse, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreia","family":"Boaro","sequence":"additional","affiliation":[{"name":"1Laborat\u00f3rio de Gen\u00e9tica e Cardiologia Molecular, Faculdade de Medicina, Instituto do Cora\u00e7\u00e3o (InCor), Hospital das Cl\u00ednicas HCFMUSP, Universidade de S\u00e3o Paulo, S\u00e3o Paulo, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavia Leticia","family":"Martins","sequence":"additional","affiliation":[{"name":"1Laborat\u00f3rio de Gen\u00e9tica e Cardiologia Molecular, Faculdade de Medicina, Instituto do Cora\u00e7\u00e3o (InCor), Hospital das Cl\u00ednicas HCFMUSP, Universidade de S\u00e3o Paulo, S\u00e3o Paulo, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thais","family":"Mauad","sequence":"additional","affiliation":[{"name":"3Departmento de Patologia, Faculdade de Medicina, Universidade de S\u00e3o Paulo, S\u00e3o Paulo, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caio A.M.","family":"Tavares","sequence":"additional","affiliation":[{"name":"4Unidade de Cardiogeriatria, Instituto do Cora\u00e7\u00e3o (InCor), Hospital das Cl\u00ednicas HCFMUSP, Faculdade de Medicina, Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"},{"name":"5Academic Research Organization (ARO), Hospital Israelita Albert Einstein, S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisete Ribeiro","family":"Teixeira","sequence":"additional","affiliation":[{"name":"6Divis\u00e3o de Pneumologia, Faculdade de Medicina, Instituto do Cora\u00e7\u00e3o (InCor), Hospital das Cl\u00ednicas HCFMUSP, Universidade de S\u00e3o Paulo, S\u00e3o Paulo, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Caramelli","sequence":"additional","affiliation":[{"name":"7Unidade de Medicina Interdisciplinar em Cardiologia, Instituto do Cora\u00e7\u00e3o (InCor), Hospital das Cl\u00ednicas HCFMUSP, Universidade de S\u00e3o Paulo, S\u00e3o Paulo, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3715-6917","authenticated-orcid":false,"given":"Adriana C.C.","family":"Girardi","sequence":"additional","affiliation":[{"name":"1Laborat\u00f3rio de Gen\u00e9tica e Cardiologia Molecular, Faculdade de Medicina, Instituto do Cora\u00e7\u00e3o (InCor), Hospital das Cl\u00ednicas HCFMUSP, Universidade de S\u00e3o Paulo, S\u00e3o Paulo, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2025,2,4]]},"reference":[{"key":"2025021308221083700_CS-2024-1166C1","doi-asserted-by":"crossref","first-page":"C82","DOI":"10.1152\/ajpcell.00287.2006","article-title":"Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system","volume":"292","author":"Mehta","year":"2007","journal-title":"Am. 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Dis."},{"key":"2025021308221083700_CS-2024-1166C30","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1164\/rccm.2108086","article-title":"Angiotensin converting enzyme insertion\/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome","volume":"166","author":"Marshall","year":"2002","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2025021308221083700_CS-2024-1166C31","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/S0002-9343(01)01071-3","article-title":"Deletion allele of the angiotensin-converting enzyme gene as a risk factor for pneumonia in elderly patients","volume":"112","author":"Morimoto","year":"2002","journal-title":"Am. J. Med."},{"key":"2025021308221083700_CS-2024-1166C32","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1164\/rccm.200309-1219OC","article-title":"Effects of an angiotensin-converting enzyme inhibitor-based regimen on pneumonia risk","volume":"169","author":"Ohkubo","year":"2004","journal-title":"Am. J. Respir. Crit. 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