Abstract P510: Nox4 Deficiency Leads to Hypertension and Vascular Damage With Enhanced Effects in Ang II-dependent Hypertension

Abstract

We previously showed that Nox1 and Nox2 are not involved in chronic Ang II-dependent hypertension, which recapitulates human hypertension. Here we questioned the role of Nox4 by studying transgenic mice expressing human renin (LinA3) crossed with Nox4-/- mice. Four groups were used: wildtype (WT), LinA3, Nox4 KO (Nox4), and LinA3/Nox4 KO (LinA3/Nox4). Blood pressure was measured by tail cuff. Aorta was collected to assess wall thickness, collagen and glycosaminoglycans (GAGs) deposition, and TNFα expression. Mesenteric arteries were used to access vascular function by myography. Blood pressure was increased in LinA3, Nox4 and LinA3/Nox4 mice vs WT (p<0.05). All three experimental groups exhibited vascular remodeling with evidence of increased fibrosis. Although LinA3 had increased aortic wall thickness (+31%), there was no significant change in collagen (10.3±3 vs. 8.5±2% in WT) and GAGs (6.6±3 vs 2.8±2% in WT) deposition (p<0.05). Nox4 mice, which presented a similar increase in wall thickness to LinA3 (+31%), had significant increase in collagen (20.6±6%) and GAGs (22.3±4%) in aorta (p<0.05). In LinA3/Nox4 mice, collagen (24.6±7%) and GAGs (37.1±10%) deposition were increased vs LinA3. TNFα was increased in LinA3 (130.4±6 a.u.) and LinA3/Nox4 mice (129±5 a.u.) vs WT (116.8±9 a.u.) (p<0.05). Mesenteric arteries from LinA3, Nox4 and LinA3/Nox4 mice, exhibit increased Phenylephrine-induced vasoconstriction vs WT (Emax: WT 6.79±0.29 vs LinA3 9.37±0.51; Nox4 9.87±1.59; LinA3/Nox4 9.12±1.63, p<0.05). Endothelium-dependent vasodilation was not reduced in Nox4 but impaired in LinA3 and LinA3/Nox4 (Emax: WT 86.48±0.01 vs LinA3 59.70±0.03; LinA3/Nox4 33.57±0.26, p<0.05). In conclusion, Nox4 deficiency was associated with increased blood pressure, vascular dysfunction and fibrosis, effects that were variably enhanced in LinA3/Nox4 mice. We also observed that the fibrosis in vessels from Nox4 mice was not associated with inflammation. These results suggest that Nox4 may be cardiovascular protective, which when downregulated leads to blood pressure elevation and vascular injury, processes that may be amplified by Ang II-dependent hypertension.