Inhibition of the Renin-Angiotensin System Fails to Suppress β-Aminopropionitrile-Induced Thoracic Aortopathy in Mice - Brief Report

Hisashi Sawada, Satoko Ohno-Urabe, Dien Ye, Michael K. Franklin, Jessica J. Moorleghen, Deborah A. Howatt, Adam E. Mullick, Alan Daugherty, Hong S. Lu

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Cross-linking of lysine residues in elastic and collagen fibers is a vital process in aortic development. Inhibition of lysyl oxidase by BAPN (β-aminopropionitrile) leads to thoracic aortopathies in mice. Although the renin-angiotensin system contributes to several types of thoracic aortopathies, it remains unclear whether inhibition of the renin-angiotensin system protects against aortopathy caused by the impairment of elastic fiber/collagen crosslinking. Methods: BAPN (0.5% wt/vol) was started in drinking water to induce aortopathies in male C57BL/6J mice at 4 weeks of age for 4 weeks. Five approaches were used to investigate the impact of the renin-angiotensin system. Bulk RNA sequencing was performed to explore potential molecular mechanisms of BAPN-induced thoracic aortopathies. Results: Losartan increased plasma renin concentrations significantly, compared with vehicle-infused mice, indicating effective angiotensin II type 1 receptor inhibition. However, losartan did not suppress BAPN-induced aortic rupture and dilatation. Since losartan is a surmountable inhibitor of the renin-angiotensin system, irbesartan, an insurmountable inhibitor, was also tested. Although increased plasma renin concentrations indicated effective inhibition, irbesartan did not ameliorate aortic rupture and dilatation in BAPN-administered mice. Thus, BAPN-induced thoracic aortopathies were refractory to angiotensin II type 1 receptor blockade. Next, we inhibited angiotensin II production by pharmacological or genetic depletion of AGT (angiotensinogen), the unique precursor of angiotensin II. However, neither suppressed BAPN-induced thoracic aortic rupture and dilatation. Aortic RNA sequencing revealed molecular changes during BAPN administration that were distinct from other types of aortopathies in which angiotensin II type 1 receptor inhibition protects against aneurysm formation. Conclusions: Inhibition of either angiotensin II action or production of the renin-angiotensin system does not attenuate BAPN-induced thoracic aortopathies in mice.

Original languageEnglish
Pages (from-to)1254-1261
Number of pages8
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume42
Issue number10
DOIs
StatePublished - Oct 1 2022

Bibliographical note

Funding Information:
This research work is supported by National Heart, Lung, and Blood Institute of the National Institutes of Health (R35HL155649) and the American Heart Association SFRN in Vascular Disease (18SFRN33900001). The content in this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2022 Ophthalmic Communications Society, Inc. Unauthorized reproduction of this article is prohibited.

Keywords

  • BAPN
  • angiotensin
  • angiotensinogen
  • aortic aneurysm
  • aortic dissection
  • renin

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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