Immune activation caused by vascular oxidation promotes fibrosis and hypertension

Abstract

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.

CD28/B7 Deficiency Attenuates Systolic Overload-Induced Congestive Heart Failure, Myocardial and Pulmonary Inflammation, and Activated T Cell Accumulation in the Heart and Lungs

“…16 Recent studies from Dr. Harrison and his associates have demonstrated that oxidized self- antigen(s) contributes to Ang-II induced T-cell activation and hypertension in mice. 17, 18 In the context that oxidative stress is increased during CHF development, oxidized proteins in heart and lungs are likely contributors to the TAC-induced T cell activation. However, it is not clear what endogenous antigen(s) mediate T-cell activation in CHF.…”

Pulmonary fibrosis in a mouse model of sarcoid granulomatosis induced by booster challenge withPropionibacterium acnes

“…IFN-γ plays a pivotal role in granulomatous inflammation; however, it may also be involved in fibrosis. In previous studies, T cell activation with release of proinflammatory cytokines such as IFN-γ and TNF-α is suggested contribute to fibrosis in the heart and kidney [28], and levels of profibrotic cytokines such as TGF-β1 and IL-1 are increased in supernatants from activated T cells [29]. Previous studies showed that fibrotic sarcoidosis was associated with activation of an immune response, which was different from the pathogenesis of IPF [30].…”

Oxidative Stress and Hypertensive Diseases

“…Chronic vascular oxidant stress also seems to enhance formation of these and their accumulation in dendritic cells. 163 …”