Angiotensin ll Type 1 Receptor (AT1) Induces Altered Vascular Responses in Allergic Mice via NOX4 and HIF‐a

Abstract

Airway diseases like asthma leads to cardiovascular disease (CVD). We have shown that in a mouse model of asthma, airway hypersensitivity is exacerbated by Angiotensin II (Ang II) via AT1 receptor activation (Am J Respir Crit Care Med. 2015;191:A5663). In this study (see graphic for hypothesis), we investigated the contribution of NOX4 to Ang II-mediated aortic responses in a mouse model of allergic asthma developed in this laboratory. The effects of NOX4 inhibitor GKT137831, HIF-1α inhibitor FM19 and thioredoxin (TRX) activator auranofin were studied on Ang-ll induced-contraction in isolated aortic rings from asthmatic mice using ex-vivo organ bath. Mice were divided into control (CON) and allergen sensitized-challenged (SEN) groups. Mice were sensitized (i.p.) on days 1, 6 with 0.2μg ovalbumin (OVA) followed by 5% OVA aerosol challenges on days 11–13. AT1 antagonist losartan was given i.p. as a single bolus dose (20mg/kg) on day 14 to SEN mice. Organ bath studies were done on day 14 and Western Blot analyses were done to determine aortic expression of AT1, NOX4 as well as p22phox, the subunits of NOX4. In the SEN group, Ang II (10μM) produced higher aortic contraction (33.48±3.26% vs vs. 18.06±3.07% in CON; p<0.05) that was lowered significantly with the use of inhibitors for HIF-1α (10μM; 13.70%±7.43%) and NOX4 (3.54%±6.61%) respectively. Studies have shown that TRX can inhibit Ang ll, HIF-1α sand NOX 4 in the vascular system. Our data showed that TRX activator (auranofin) inhibited Ang ll-mediated contraction to a greater extent in CON mice than SEN. Aortic AT1 receptor expression was significantly higher in SEN mice (1.74±0.08) than CON (1.00±0.13). The expression of NOX4 (1.27±0.06 vs. 0.99±0.09) and p22phox (3.45±0.35 vs. 1.35±0.62) were significantly higher in SEN mice compared to CON. Treatment with losartan significantly attenuated the increases in NOX4 (from1.27±0.06 to 0.67±0.11) and p22phox (from 3.45±0.35 to 0.26±0.11) in SEN mice. These data suggest that most Ang ll through HIF-1α and upregulation by Nox 4, may contribute to altered vascular responses in allergic mice, while TRX antioxidant effect is lower in SEN mice. AT1 antagonist losartan reverses all of these effects, and thus may prevent altered vascular responses to Ang ll in asthma. Support or Funding Information Institutional Research Grant Long Island University SCHEMATIC REPRESENTATION OF HYPOTHESIS TESTED AND PROPOSED PATHWAY FOR ANG ll-MEDIATED VASCULAR CONTRACTION IN ASTHMA This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.