Abstract 354: Vascular Oxidative Stress Promotes Aortic Stiffening In Hypertension

Abstract

We have previously shown that T cells and the cytokine IL-17a contribute to aortic stiffening in hypertension. Because oxidative stress also contributes to hypertension, we sought to determine if chronic oxidative stress causes aortic stiffening and to determine if T cells are involved. We studied tgsm/p22phox mice, which have an overexpression of the NADPH oxidase subunit p22phox in the vascular smooth muscle and approximately 2-fold increase vascular reactive oxygen species (ROS). Six month-old tgsm/p22phox mice were normotensive at baseline but exhibited increased aortic stiffness as indicated by the leftward shift of stress-strain curves (p<0.05). Aortic collagen content, as determined by hydroxyproline assay, was also increased in these mice compared to age-matched C57Bl/6 mice (76.3±11.9 vs. 43.2±11.9 ng/μg total protein, p<0.01). At nine months of age, aortic stiffening did not further increase but tgsm/p22phox mice developed vascular inflammation and mild hypertension (137±9 systolic and 100±7 diastolic, p<0.05), indicating that aortic stiffening precedes hypertension. Surprisingly, T cells isolated from the spleen of 9 month-old Tgsm/p22phox mice demonstrated marked production of IL-17a and IFN-gamma. To determine if inflammation contributes to these pathological events, we crossed the tgsm/p22phox mice with RAG-1-/- mice. The resultant mice were protected from vascular inflammation, aortic stiffening and hypertension. Tempol, a superoxide dismutase mimetic, normalized blood pressure (109±4 systolic and 95±4 diastolic, p<0.05), reduced vascular collagen deposition (37.5±9.5 ng/μg total protein, p<0.01) and prevented aortic stiffening in tgsm/p22phox mice. We have recently shown that isoketals, which are oxidation products of arachidonic acid, promote T cell activation. Treatment with the isoketal scavenger 2-hydroxybenzylamine also normalized blood pressure, prevented collagen deposition and aortic stiffening in 9 month-old tgsm/p22phox mice. These data are compatible with a pathway in which vascular oxidative stress leads to formation of isoketals, which promote T cell activation, production of cytokines such as IL-17a and IFN-gamma, which in turn promote collagen deposition and aortic stiffening.