{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T23:42:37Z","timestamp":1777592557521,"version":"3.51.4"},"reference-count":38,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T00:00:00Z","timestamp":1639958400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Compound 21 (C21), an AT2 receptor agonist, and Angiotensin 1-7 (Ang 1-7), through Mas receptor, play an important role in the modulation of the protective arm of the renin-angiotensin system. The aim of this study was to investigate in an experimental model of angiotensin II-dependent hypertension whether the activation of the potentially protective arm of the renin-angiotensin system, through AT2 or Mas receptor stimulation, counteracts the onset of myocardial fibrosis and hypertrophy, and whether these effects are mediated by inflammatory mechanism and\/or sympathetic activation. Sprague Dawley rats (n = 67) were treated for 1 (n = 25) and 4 (n = 42) weeks and divided in the following groups: (a) Angiotensin II (Ang II, 200 ng\/kg\/min, osmotic minipumps, sub cutis); (b) Ang II+Compound 21 (C21, 0.3 mg\/kg\/day, intraperitoneal); (c) Ang II+Ang 1-7 (576 \u00b5g\/kg\/day, intraperitoneal); (d) Ang II+Losartan (50 mg\/kg\/day, per os); (e) control group (physiological saline, sub cutis). Systolic blood pressure was measured by tail cuff method and, at the end of the experimental period, the rats were euthanized and the heart was excised to evaluate myocardial fibrosis, hypertrophy, inflammatory cell infiltration and tyrosine hydroxylase expression, used as marker of sympathetic activity. Ang II caused a significant increase of blood pressure, myocardial interstitial and perivascular fibrosis and myocardial hypertrophy, as compared to control groups. C21 or Ang 1-7 administration did not modify the increase in blood pressure in Ang II treated rats, but both prevented the development of myocardial fibrosis and hypertrophy. Treatment with losartan blocked the onset of hypertension and myocardial fibrosis and hypertrophy in Ang II treated rats. Activation of AT2 receptors or Mas receptors prevents the onset of myocardial fibrosis and hypertrophy in Ang II-dependent hypertension through the reduction of myocardial inflammatory cell infiltration and tyrosine hydroxylase expression. Unlike what happens in case of treatment with losartan, the antifibrotic and antihypertrophic effects that follow the activation of the AT2 or Mas receptors are independent on the modulation of blood pressure.<\/jats:p>","DOI":"10.3390\/ijms222413678","type":"journal-article","created":{"date-parts":[[2021,12,21]],"date-time":"2021-12-21T04:23:47Z","timestamp":1640060627000},"page":"13678","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Angiotensin Type 2 and Mas Receptor Activation Prevents Myocardial Fibrosis and Hypertrophy through the Reduction of Inflammatory Cell Infiltration and Local Sympathetic Activity in Angiotensin II-Dependent Hypertension"],"prefix":"10.3390","volume":"22","author":[{"given":"Giovanna","family":"Castoldi","sequence":"first","affiliation":[{"name":"Dipartimento di Medicina e Chirurgia, Universit\u00e0 degli Studi di Milano-Bicocca, 20900 Monza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raffaella","family":"Carletti","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Traslazionale e di Precisione, Sapienza Universita\u2019 di Roma, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Ippolito","sequence":"additional","affiliation":[{"name":"Laboratorio Analisi Chimico Cliniche, Ospedale San Gerardo, ASST Monza, 20900 Monza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Stella","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina e Chirurgia, Universit\u00e0 degli Studi di Milano-Bicocca, 20900 Monza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6181-089X","authenticated-orcid":false,"given":"Gianpaolo","family":"Zerbini","sequence":"additional","affiliation":[{"name":"Unita Complicanze del Diabete, IRCCS Istituto Scientifico San Raffaele, 20132 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9902-9641","authenticated-orcid":false,"given":"Sara","family":"Pelucchi","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina e Chirurgia, Universit\u00e0 degli Studi di Milano-Bicocca, 20900 Monza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanni","family":"Zatti","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina e Chirurgia, Universit\u00e0 degli Studi di Milano-Bicocca, 20900 Monza, Italy"},{"name":"Clinica Ortopedica, Ospedale San Gerardo, ASST Monza, 20900 Monza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4696-0560","authenticated-orcid":false,"given":"Cira R. T.","family":"di Gioia","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Radiologiche, Oncologiche e Anatomopatologiche, Istituto di Anatomia Patologica, Sapienza Universita\u2019 di Roma, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1161\/CIRCRESAHA.116.303587","article-title":"Hypertension: Renin-angiotensin-aldosterone system alterations","volume":"116","author":"Roks","year":"2015","journal-title":"Circ. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1953","DOI":"10.1097\/HJH.0000000000001940","article-title":"2018 ESC\/ESH Guidelines for the management of arterial hypertension. 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