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Title page for ETD etd-11042014-141150


Type of Document Dissertation
Author Wu, Jing
Author's Email Address jing.wu@vanderbilt.edu
URN etd-11042014-141150
Title The Roles of Oxidative Stress, Inflammation and Adaptive Immunity in Aortic Stiffening
Degree PhD
Department Pharmacology
Advisory Committee
Advisor Name Title
Italo O. Biaggioni, M.D. Committee Chair
Billy G. Hudson, Ph.D. Committee Member
Bjorn C. Knollmann, M.D., Ph.D. Committee Member
David G. Harrison, M.D. Committee Member
Sean S. Davies, Ph.D. Committee Member
Keywords
  • oxidative stress
  • inflammation
  • immunity
  • aortic stiffening
Date of Defense 2014-10-29
Availability unrestricted
Abstract
Aortic stiffening is an important cause of systolic hypertension and predispose to cardiovascular morbidity and mortality. The precise mechanisms underlying aortic stiffening remain undefined. Using multiple genetically modified mouse models, I performed a series of studies to investigate the roles of oxidation, inflammation and T cell-mediated adaptive immunity in the development of this pathological condition. I found that pro-inflammatory cytokines such as IL-17A released by activated T cells, in concert with increased mechanical stretch, promote the production of collagen by arterial fibroblasts in hypertension. These effects occur in a p38 MAP kinase-dependent manner and pharmacological inhibition of this enzyme lowers blood pressure and prevents aortic stiffening in angiotensin II-infused mice. To understand the mechanism of T cell activation in hypertension, I employed murine models of chronic vascular oxidative stress. Tgsmp22phox mice and SOD3loxp/loxp X Tgsmmhc/cre exhibited aged-related vascular inflammation, aortic stiffening and hypertension. Isoketal-protein adducts accumulated in aortas of tgsm/p22phox mice, forming immunogenic neoantigens. I found these are presented by dendritic cells to T cells, leading to T cell proliferation, cytokine production and infiltration of T cells to vessels, the original site of oxidant injury. Activated T cells release cytokines, including IL-17A and IFN-γ, which have previously been shown to induce the expression of chemokines. Cellular components, including vascular Sca-1+ progenitors acquire fibroblast-like phenotype and, along with collagen I+CD45+ circulating fibrocytes, become important contributors of adventitial collagen deposition and aortic stiffening. These studies demonstrate that there is interplay between chronic vascular oxidative stress, inflammation and adaptive immune cells in the pathogenesis of aortic stiffening and hypertension.
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