TY - JOUR
T1 - Immune activation caused by vascular oxidation promotes fibrosis and hypertension
AU - Wu, Jing
AU - Saleh, Mohamed A.
AU - Kirabo, Annet
AU - Itani, Hana A.
AU - Montaniel, Kim Ramil C.
AU - Xiao, Liang
AU - Chen, Wei
AU - Mernaugh, Raymond L.
AU - Cai, Hua
AU - Bernstein, Kenneth E.
AU - Goronzy, Jörg J.
AU - Weyand, Cornelia M.
AU - Curci, John A.
AU - Barbaro, Natalia R.
AU - Moreno, Heitor
AU - Davies, Sean S.
AU - Roberts, L. Jackson
AU - Madhur, Meena S.
AU - Harrison, David G.
N1 - Funding Information:
We are grateful to the Transitional Pathology Shared Resource (TPSR) core and the Epithelial Biology Center at Vanderbilt University for assistance with imaging and quantification of immunohistochemical staining. We also thank the Vanderbilt University Medical Center Hormone Assay and Analytical Services Core (supported by NIH grants DK059637 and DK020593), who performed the cytokine measurements. We thank William Zackert for performing the MS and IHC for isoketal in the aorta samples. We also thank Zhizhang Wang in the Division of Cardiovascular Medicine at Vanderbilt University for his assistance in conducting in vivo measurement of PWV. This work was supported by NIH R01 grants HL105294, HL039006, and HL108701; VITA contract HHSN268201400010C; Program Project grants P01 HL58000 and GM015431; an American Heart Association predoctoral fellowship to J. Wu (13PRE14480008); and postdoctoral fellowship awards to A. Kirabo and M.A. Saleh. M.S. Madhur is the recipient of NIH K08 award (1K08HL121671) and a Vanderbilt Physician Scientist Development Award. H.A. Itani is supported by NIH F32 training grant (1F32HL124972-01).
PY - 2016/1/4
Y1 - 2016/1/4
N2 - Vascular oxidative injury accompanies many common conditions associated with hypertension. In the present study, we employed mouse models with excessive vascular production of ROS (tgsm/p22phox mice, which overexpress the NADPH oxidase subunit p22phox 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 tgsm/p22phox mice produced high levels of IL-17A and IFN-γ. Crossing tgsm/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 tgsm/p22phox mice. Autologous pulsing with tgsm/p22phox aortic homogenates promoted DCs of tgsm/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.
AB - Vascular oxidative injury accompanies many common conditions associated with hypertension. In the present study, we employed mouse models with excessive vascular production of ROS (tgsm/p22phox mice, which overexpress the NADPH oxidase subunit p22phox 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 tgsm/p22phox mice produced high levels of IL-17A and IFN-γ. Crossing tgsm/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 tgsm/p22phox mice. Autologous pulsing with tgsm/p22phox aortic homogenates promoted DCs of tgsm/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.
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U2 - 10.1172/JCI80761
DO - 10.1172/JCI80761
M3 - Article
C2 - 26595812
AN - SCOPUS:84956708183
SN - 0021-9738
VL - 126
SP - 50
EP - 67
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 1
ER -