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Vascular smooth muscle cell peroxisome proliferator-activated receptor ? protects against endothelin-1-induced oxidative stress and inflammation.

ABSTRACT: AIMS:Peroxisome proliferator-activated receptor ? (PPAR?) agonists reduce blood pressure and vascular injury in hypertensive rodents. Ppar? inactivation in vascular smooth muscle cells (VSMC) enhances vascular injury. Transgenic mice overexpressing endothelin (ET)-1 selectively in the endothelium (eET-1) exhibit endothelial dysfunction, increased oxidative stress and inflammation. We hypothesized that inactivation of the Ppar? gene in VSMC (smPpar?-/-) would exaggerate ET-1-induced vascular injury. METHODS AND RESULTS:eET-1, smPpar?-/- and eET-1/smPpar?-/- mice were treated with tamoxifen for 5 days and studied 4 weeks later. SBP was higher in eET-1 and unaffected by smPpar? inactivation. Mesenteric artery vasodilatory responses to acetylcholine were impaired only in smPpar?-/-. N(omega)-Nitro-L-arginine methyl ester abrogated relaxation responses, and the Ednra/Ednrb mRNA ratio was decreased in eET-1/smPpar?-/-, which could indicate that nitric oxide production was enhanced by ET-1 stimulation of endothelin type B receptors. Mesenteric artery media/lumen was greater only in eET-1/smPpar?-/-. Mesenteric artery reactive oxygen species increased in smPpar? and were further enhanced in eET-1/smPpar?-/-. Perivascular fat monocyte/macrophage infiltration was higher in eET-1 and smPpar? and increased further in eET-1/smPpar?-/-. Spleen CD11b+ cells were increased in smPpar?-/- and further enhanced in eET-1/smPpar?-/-, whereas Ly-6C(hi) monocytes increased in eET-1 and smPpar?-/- but not in eET-1/smPpar?-/-. Spleen T regulatory lymphocytes increased in smPpar? and decreased in eET-1, and decreased further in eET-1/smPpar?-/-. CONCLUSION:VSMC Ppar? inactivation exaggerates ET-1-induced vascular injury, supporting a protective role for PPAR? in hypertension through modulation of pro-oxidant and proinflammatory pathways. Paradoxically, ET-1 overexpression preserved endothelial function in smPpar?-/- mice, presumably by enhancing nitric oxide through stimulation of endothelin type B receptors.

SUBMITTER: Idris-Khodja N

PROVIDER: S-EPMC6338076 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Vascular smooth muscle cell peroxisome proliferator-activated receptor γ protects against endothelin-1-induced oxidative stress and inflammation.

Idris-Khodja Noureddine N Ouerd Sofiane S Trindade Michelle M Gornitsky Jordan J Rehman Asia A Barhoumi Tlili T Offermanns Stefan S Gonzalez Frank J FJ Neves Mario F MF Paradis Pierre P Schiffrin Ernesto L EL

Journal of hypertension 20170701 7

<h4>Aims</h4>Peroxisome proliferator-activated receptor γ (PPARγ) agonists reduce blood pressure and vascular injury in hypertensive rodents. Pparγ inactivation in vascular smooth muscle cells (VSMC) enhances vascular injury. Transgenic mice overexpressing endothelin (ET)-1 selectively in the endothelium (eET-1) exhibit endothelial dysfunction, increased oxidative stress and inflammation. We hypothesized that inactivation of the Pparγ gene in VSMC (smPparγ-/-) would exaggerate ET-1-induced vascu ...[more]

PMID: 28234672

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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

Vascular smooth muscle cell peroxisome proliferator-activated receptor ? protects against endothelin-1-induced oxidative stress and inflammation.

Publications

Vascular smooth muscle cell peroxisome proliferator-activated receptor γ protects against endothelin-1-induced oxidative stress and inflammation.

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