NADPH oxidase mediates altered vascular responses in allergic mice (1065.10)

Abstract

Asthma is associated with adverse cardiovascular outcomes, though the cause is unclear. We have shown vascular inflammation and altered vascular responses in allergic mice (Ponnoth et al., AJP 2008, 2010). In this study, we investigated the contribution of NADPH oxidase to angiotensin II (Ang II)‐mediated aortic responses in a mouse model of allergic asthma developed in this laboratory. 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. Ang II type 1 receptor (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, NOX 1, 2 and 4 as well as p22phox and p67phox, the subunits of NOX. In the SEN group, Ang II (10μM) produced higher aortic contraction (33.48±3.26% vs. 18.06±3.07% in CON; p<0.05) that was lowered with the use of apocynin (10μM; 33.48±3.26% vs.13.11±6.89), while no effect was observed in CON. SEN mice had lower endothelial response to acetylcholine (30.95±5.73% vs. 57.6±4.3% in CON; p<0.05), that was improved with i.p. losartan (56.1±4.39%). AT1 expression was unchanged in SEN mice. However, 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 (from3.45±0.35 to 0.26±0.11) in SEN mice. These data suggest that most likely NOX4, through p22phox association, may contribute to altered Ang ll and endothelial responses in allergic mice, and that losartan can improve these outcomes.Grant Funding Source: Supported by HL027339, HL094447