Inhibition of Angiotensin II Dependent AT1a Receptor Stimulation Attenuates Thoracic Aortic Pathology in Fibrillin-1^C1041G/+Mice

Abstract

246 words Manuscript: 4100 words Number of Figures: 5 Supplemental Figures: 8 TOC category Basic TOC subcategory: Vascular Biology Highlights • Profound sexual dimorphism of aortic disease occurs in Fbn1 C1041G/+ mice, with female mice being more resistant and male mice being more susceptible. • Inhibition of the AngII-AT1aR axis attenuates aortic pathology in male Fbn1 C1041G/+ mice. • Antisense oligonucleotides targeting angiotensinogen deplete plasma angiotensinogen and attenuate thoracic aortic aneurysms. Graphic Abstract Abstract Objective:A cardinal feature of Marfan syndrome is thoracic aortic aneurysm (TAA). The contribution of ligand-dependent stimulation of angiotensin II receptor type 1a (AT1aR) to TAA progression remains controversial because the beneficial effects of angiotensin receptor blockers have been ascribed to off-target effects. This study used genetic and pharmacologic modes of attenuating angiotensin receptor and ligand, respectively, to determine their roles on TAA in mice with fibrillin-1 haploinsufficiency (Fbn1 C1041G/+ ). Approach and Results:TAA in Fbn1 C1041G/+ mice were determined in both sexes and found to be strikingly sexual dimorphic. Males displayed progressive dilation over 12 months while ascending aortic dilation in Fbn1 C1041G/+ females did not differ significantly from wild type mice. To determine the role of AT1aR, Fbn1 C1041G/+ mice that were either +/+ or -/-for AT1aR were generated. AT1aR deletion reduced progressive 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 (AGT-ASO) was administered to male Fbn1 C1041G/+ mice to determine the effects of angiotensin II depletion. AGT-ASO administration, at doses that markedly reduced plasma AGT concentrations, attenuated progressive dilation of the ascending aorta and aortic root. AGT-ASO also reduced medial thickening and elastin fragmentation. Conclusions:Genetic approaches to delete AT1aR and deplete AngII production exerted similar effects in attenuating pathology in the proximal thoracic aorta of male Fbn1 C1041G/+ mice. These data are consistent with ligand (AngII) dependent stimulation of AT1aR being responsible for aortic disease progression.

Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies

“…In contrast with direct TGF-β antagonism, treatment with antagonists of AT 1 R signaling, such as the angiotensin receptor blocker (ARB) losartan, invariably prevents the development of aneurysm in animal models; this beneficial effect associates with reduced levels of TGFβ ligand, pSmad2/3, and the expression of TGF-β target genes [117,143,159,313,[434][435][436]. In addition, the deletion of Agtr1a (gene encoding AT 1 R in mice) prevents aortic root dilation in two different MFS mouse models [437,438]. The beneficial effects of AT 1 R antagonism in mouse models of TAA have been attributed to its anti-hypertensive effects and to the inhibition of fibrotic, hypertrophic, and mitogenic responses activated by TGF-β and mitogen-activated protein kinase (MAPK) signaling [159,258,432,439].…”