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Chlorotyrosine promotes human aortic smooth muscle cell migration through increasing superoxide anion production and ERK1/2 activation.

ABSTRACT: Chlorotyrosine is an oxidative product of hypochlorous acid and l-tyrosine, and is considered as a biomarker for oxidative stress and cardiovascular disease. However, it is not clear whether chlorotyrosine could directly contribute to vascular pathogenesis. In this study, we investigated the effect and potential mechanisms of chlorotyrosine on human aortic smooth muscle cell (AoSMC) migration. With Boyden chamber and wound healing assays, chlorotyrosine significantly increased AoSMC migration in a concentration- and time-dependent manner. In addition, chlorotyrosine significantly increased the expression of several key molecules related to cell migration including PDGF receptor-B (PDGFR-B), matrix metalloproteinases (MMP-1 and MMP-2) and integrins (alpha3, alphaV, and beta3) in AoSMC at both mRNA and protein levels. Furthermore, chlorotyrosine also increased superoxide anion generation in AoSMC with the fluorescent dye dihydroethidium (DHE) staining. Activation of mitogen-activated protein kinases (MAPKs) was analyzed with Bio-Plex Luminex immunoassay and Western blotting. Chlorotyrosine induced a transient phosphorylation of ERK1/2, but not JNK and p38 MAPKs. Antioxidants including selenomethionine (SeMet) and Mn(III) tetrakis (4-benzoic acid) porphyrin (MnTBAP) as well as ERK1/2 inhibitor PD98059 effectively blocked chlorotyrosine-induced AoSMC migration. Thus, these findings demonstrate new biological functions of chlorotyrosine in human SMC migration, which may play a crucial role in the vascular lesion formation.

SUBMITTER: Mu H

PROVIDER: S-EPMC2924162 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Chlorotyrosine promotes human aortic smooth muscle cell migration through increasing superoxide anion production and ERK1/2 activation.

Mu Hong H Wang Xinwen X Lin Peter H PH Yao Qizhi Q Chen Changyi C

Atherosclerosis 20080220 1

Chlorotyrosine is an oxidative product of hypochlorous acid and l-tyrosine, and is considered as a biomarker for oxidative stress and cardiovascular disease. However, it is not clear whether chlorotyrosine could directly contribute to vascular pathogenesis. In this study, we investigated the effect and potential mechanisms of chlorotyrosine on human aortic smooth muscle cell (AoSMC) migration. With Boyden chamber and wound healing assays, chlorotyrosine significantly increased AoSMC migration in ...[more]

PMID: 18281051

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Project description:Peroxisome proliferator-activated receptor-? (PPAR?) plays an important role in the vasculature; however, the role of PPAR? in abdominal aortic aneurysms (AAA) is not well understood. We hypothesized that PPAR? in smooth muscle cells (SMCs) attenuates the development of AAA. We also investigated PPAR?-mediated signaling pathways that may prevent the development of AAA.We determined whether periaortic application of CaCl(2) renders vascular SMC-selective PPAR? knockout (SMPG KO) mice more susceptible to destruction of normal aortic wall architecture.There is evidence of increased vessel dilatation in the abdominal aorta 6 weeks after 0.25M periaortic CaCl(2) application in SMPG KO mice compared with littermate controls (1.4 ± 0.3 mm [n = 8] vs 1.1 ± 0.2 mm [n = 7]; P = .000119). Results from SMPG KO mice indicate medial layer elastin degradation was greater 6 weeks after abluminal application of CaCl(2) to the abdominal aorta (P < .01). Activated cathepsin S, a potent elastin-degrading enzyme, was increased in SMPG KO mice vs wild-type controls. To further identify a role of PPAR? signaling in reducing the development of AAA, we demonstrated that adenoviral-mediated PPAR? overexpression in cultured rat aortic SMCs decreases (P = .022) the messenger RNA levels of cathepsin S. In addition, a chromatin immunoprecipitation assay detected PPAR? bound to a peroxisome proliferator-activated receptor response element (PPRE) -141 to -159 bp upstream of the cathepsin S gene sequence in mouse aortic SMCs. Also, adenoviral-mediated PPAR? overexpression and knockdown in cultured rat aortic SMCs decreases (P = .013) and increases (P = .018) expression of activated cathepsin S. Finally, immunohistochemistry demonstrated a greater inflammatory infiltrate in SMPG KO mouse aortas, as evidenced by elevations in F4/80 and tumor necrosis factor-? expression.In this study, we identify PPAR? as an important contributor in attenuating the development of aortic aneurysms by demonstrating that loss of PPAR? in vascular SMCs promotes aortic dilatation and elastin degradation. Thus, PPAR? activation may be potentially promising medical therapy in reducing the risk of AAA progression and rupture.

Dataset Information

Chlorotyrosine promotes human aortic smooth muscle cell migration through increasing superoxide anion production and ERK1/2 activation.

Publications

Chlorotyrosine promotes human aortic smooth muscle cell migration through increasing superoxide anion production and ERK1/2 activation.

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