Objective: A cardinal feature of Marfan syndrome is thoracic aortic aneurysm. The contribution of the renin-angiotensin system via AT1aR (Ang II [angiotensin II] receptor type 1a) to thoracic aortic aneurysm progression remains controversial because the beneficial effects of angiotensin receptor blockers have been ascribed to off-target effects. This study used genetic and pharmacological modes of attenuating angiotensin receptor and ligand, respectively, to determine their roles on thoracic aortic aneurysm in mice with fibrillin-1 haploinsufficiency (Fbn1C1041G/+). Approach and Results: Thoracic aortic aneurysm in Fbn1C1041G/+mice was found to be strikingly sexual dimorphic. Males displayed aortic dilation over 12 months while aortic dilation in Fbn1C1041G/+females did not differ significantly from wild-type mice. To determine the role of AT1aR, Fbn1C1041G/+mice that were either +/+ or -/- for AT1aR were generated. AT1aR deletion reduced expansion of ascending aorta and aortic root diameter from 1 to 12 months of age in males. Medial thickening and elastin fragmentation were attenuated. An antisense oligonucleotide against angiotensinogen was administered to male Fbn1C1041G/+mice to determine the effects of Ang II depletion. Antisense oligonucleotide against angiotensinogen administration attenuated dilation of the ascending aorta and aortic root and reduced extracellular remodeling. Aortic transcriptome analyses identified potential targets by which inhibition of the renin-angiotensin system reduced aortic dilation in Fbn1C1041G/+mice. Conclusions: Deletion of AT1aR or inhibition of Ang II production exerted similar effects in attenuating pathologies in the proximal thoracic aorta of male Fbn1C1041G/+mice. Inhibition of the renin-angiotensin system attenuated dysregulation of genes within the aorta related to pathology of Fbn1C1041G/+mice.
|Number of pages||13|
|Journal||Arteriosclerosis, Thrombosis, and Vascular Biology|
|State||Published - Oct 1 2021|
Bibliographical noteFunding Information:
The authors’ research work is supported by the American Heart Association (AHA) SFRN in Vascular Disease (18SFRN33960163) and the National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (NHLBI) under award numbers R01HL133723. J.Z. Chen and M.B. Sheppard have been supported by NCATS UL1TR001998 and J.Z. Chen has been supported by NHLBI F30 HL143943. H. Sawada was supported by an AHA postdoctoral fellowship (18POST33990468). The content in this article is solely the responsibility of the authors and does not necessarily represent the official views of the American Heart Association or the National Institutes of Health.
© 2021 Lippincott Williams and Wilkins. All rights reserved.
- Marfan syndrome
- angiotensin II
- aortic aneurysm
- renin-angiotensin system
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine