4.7 Article

Distinct Mechanisms of beta-Arrestin-Biased Agonist and Blocker of AT1R in Preventing Aortic Aneurysm and Associated Mortality

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HYPERTENSION
卷 80, 期 2, 页码 385-402

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LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/HYPERTENSIONAHA.122.19232

关键词

aortic aneurysm; beta; arrestin; biased ligand; cell proliferation; proteostasis; receptor; AT1R

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This study found that using TRV027 can prevent the progression of aortic aneurysm by different mechanisms compared to the commonly used AT1R blocker, Olmesartan. TRV027 can increase aortic wall thickness, elastin content, and DNA and protein synthesis, while also preventing endoplasmic reticulum stress, fibrosis, and vasomotor hyperresponsiveness.
Background: Aortic aneurysm (AA) is a silent killer human disease with no effective treatment. Although the therapeutic potential of various pharmacological agents have been evaluated, there are no reports of beta-arrestin-biased AT1R (angiotensin-II type-1 receptor) agonist (TRV027) used to prevent the progression of AA.Methods: We tested the hypothesis that TRV027 infusion in AngII (angiotensin II)-induced mouse model of AA prevents AA. High-fat-diet-fed ApoE (apolipoprotein E gene)-null mice were infused with AngII to induce AA and co-infused with TRV027 and a clinically used AT1R blocker Olmesartan to prevent AA. Aortas explanted from different ligand infusion groups were compared with assess different grades of AA or lack of AA.Results: AngII produced AA in asymptotic to 67% male mice with significant mortality associated with AA rupture. We observed asymptotic to 13% mortality due to aortic arch dissection without aneurysm in male mice. AngII-induced AA and mortality was prevented by co-infusion of TRV027 or Olmesartan, but through different mechanisms. In TRV027 co-infused mice aortic wall thickness, elastin content, new DNA, and protein synthesis were higher than untreated and Olmesartan co-infused mice. Co-infusion with both TRV027 and Olmesartan prevented endoplasmic reticulum stress, fibrosis, and vasomotor hyper responsiveness.Conclusions: TRV027-engaged AT1R prevented AA and associated mortality by distinct molecular mechanisms compared with the AT1R blocker, Olmesartan. Developing novel beta-arrestin-biased AT1R ligands may yield promising drugs to combat AA.

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