التفاصيل البيبلوغرافية
| العنوان: |
Distinct Mechanisms of β-Arrestin-Biased Agonist and Blocker of AT1R in Preventing Aortic Aneurysm and Associated Mortality. |
| المؤلفون: |
Jara, Zaira Palomino, Harford, Terri J., Singh, Khuraijam Dhanachandra, Desnoyer, Russell, Kumar, Avinash, Srinivasan, Dasarathy, Karnik, Sadashiva S., Harford, Terri |
| المصدر: |
Hypertension (0194911X); Feb223, Vol. 80 Issue 2, p385-402, 18p |
| مستخلص: |
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 β-arrestin-biased AT1R agonist (TRV027) used to prevent the progression of AA.Methods: We tested the hypothesis that TRV027 infusion in AngII-induced mouse model of AA prevents AA. High-fat-diet-fed ApoE-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 ≈67% male mice with significant mortality associated with AA rupture. We observed ≈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 β-arrestin-biased AT1R ligands may yield promising drugs to combat AA. [ABSTRACT FROM AUTHOR] |
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