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

4 Scopus citations

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

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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