Vascular oxidative stress leads to the formation of immunogenic isoketal-protein adducts that activate T cells, promoting vascular inflammation, aortic stiffening, and hypertension.
Does scavenging superoxide or isoketals prevent vascular inflammation, aortic stiffening, and hypertension in mouse models of chronic vascular oxidative stress?
Vascular oxidative stress drives the formation of isoketal-protein adducts that activate dendritic cells and T cells, leading to aortic stiffening and hypertension, a pathway that can be blocked by specific scavengers.
Absolute Event Rate: 17.7% vs 10.7%
p-value: p=<0.05
Vascular oxidative injury accompanies many common conditions associated with hypertension. In the present study, we employed mouse models with excessive vascular production of ROS (tg(sm/p22phox) mice, which overexpress the NADPH oxidase subunit p22(phox) in smooth muscle, and mice with vascular-specific deletion of extracellular SOD) and have shown that these animals develop vascular collagen deposition, aortic stiffening, renal dysfunction, and hypertension with age. T cells from tg(sm/p22phox) mice produced high levels of IL-17A and IFN-γ. Crossing tg(sm/p22phox) mice with lymphocyte-deficient Rag1(-/-) mice eliminated vascular inflammation, aortic stiffening, renal dysfunction, and hypertension; however, adoptive transfer of T cells restored these processes. Isoketal-protein adducts, which are immunogenic, were increased in aortas, DCs, and macrophages of tg(sm/p22phox) mice. Autologous pulsing with tg(sm/p22phox) aortic homogenates promoted DCs of tg(sm/p22phox) mice to stimulate T cell proliferation and production of IFN-γ, IL-17A, and TNF-α. Treatment with the superoxide scavenger tempol or the isoketal scavenger 2-hydroxybenzylamine (2-HOBA) normalized blood pressure; prevented vascular inflammation, aortic stiffening, and hypertension; and prevented DC and T cell activation. Moreover, in human aortas, the aortic content of isoketal adducts correlated with fibrosis and inflammation severity. Together, these results define a pathway linking vascular oxidant stress to immune activation and aortic stiffening and provide insight into the systemic inflammation encountered in common vascular diseases.
Wu et al. (2015) studied Hypertension and aortic stiffening (n=43). Hypertension (human cohort) / Vascular oxidative stress (mice) vs. Normotensive subjects / Wild-type mice was evaluated on Plasma F2-isoprostanes (ng/ml) (p=<0.05). Vascular oxidative stress leads to the formation of immunogenic isoketal-protein adducts that activate T cells, promoting vascular inflammation, aortic stiffening, and hypertension.