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

Idris-Khodja, Noureddinea,*; Ouerd, Sofianea,*; Trindade, Michellea,c; Gornitsky, Jordana; Rehman, Asiaa; Barhoumi, Tlilia; Offermanns, Stefand; Gonzalez, Frank J.e; Neves, Mario F.c; Paradis, Pierrea; Schiffrin, Ernesto L.a,b

doi: 10.1097/HJH.0000000000001324
ORIGINAL PAPERS: Blood vessels

Aims: 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 vascular injury.

Methods and results: eET-1, smPparγ−/− and eET-1/smPparγ−/− mice were treated with tamoxifen for 5 days and studied 4 weeks later. SBP was higher in eET-1 and unaffected by smPparγ inactivation. Mesenteric artery vasodilatory responses to acetylcholine were impaired only in smPparγ−/−. Nω-Nitro-L-arginine methyl ester abrogated relaxation responses, and the Ednra/Ednrb mRNA ratio was decreased in eET-1/smPparγ/, 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/smPparγ/. Mesenteric artery reactive oxygen species increased in smPparγ/ and were further enhanced in eET-1/smPparγ/. Perivascular fat monocyte/macrophage infiltration was higher in eET-1 and smPparγ/ and increased further in eET-1/smPparγ/. Spleen CD11b+ cells were increased in smPparγ/ and further enhanced in eET-1/smPparγ/, whereas Ly-6Chi monocytes increased in eET-1 and smPparγ/ but not in eET-1/smPparγ/. Spleen T regulatory lymphocytes increased in smPparγ/ and decreased in eET-1, and decreased further in eET-1/smPparγ/.

Conclusion: VSMC Pparγ inactivation exaggerates ET-1-induced vascular injury, supporting a protective role for PPARγ in hypertension through modulation of pro-oxidant and proinflammatory pathways. Paradoxically, ET-1 overexpression preserved endothelial function in smPparγ−/− mice, presumably by enhancing nitric oxide through stimulation of endothelin type B receptors.

aHypertension and Vascular Research Unit, Lady Davis Institute for Medical Research

bDepartment of Medicine, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, Quebec, Canada

cDepartment of Clinical Medicine, State University of Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil

dDepartment of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany

eLaboratory of Metabolism, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

*Noureddine Idris-Khodja and Sofiane Ouerd contributed equally to the article.

Correspondence of Ernesto L. Schiffrin, C.M., MD, PhD, FRSC, FRCPC, Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital, #B-127, 3755 Côte-Ste-Catherine Rd., Montreal, QC, Canada H3T 1E2. Tel: +1 514 340 7538; fax: +1 514 340 7539; e-mail:

Abbreviations: Arg-1, arginase-1; ANOVA, analysis of variance; BP, blood pressure; CD206, mannose receptor; CreERT2, tamoxifen-inducible Cre recombinase fused with a modified estrogen receptor ligand-binding domain; DHE, dihydroethidium; eET-1, transgenic mice constitutively overexpressing human ET-1 selectively in the endothelium; eNOS, endothelial nitric oxide synthase; ET, endothelin; ETA, endothelin type A; ETB, endothelin type B; FABP4, fatty acid binding protein 4; FOXP3, forkhead box P3; iNOS, inducible nitric oxide synthase; L-NAME, Nω-nitro-L-arginine methyl ester; MA, mesenteric artery; MCP-1, monocyte chemotactic protein-1; MHC-II, major histocompatibility complex class II; MOMA-2, monocyte/macrophage antigen-2; NE, norepinephrine; NO, nitric oxide; PPARγ, peroxisome proliferator-activated receptor gamma; PVAT, perivascular adipose tissue; ROS, reactive oxygen species; Rps16, ribosomal protein S16; smPparγ−/−, inactivation of the Pparγ gene in VSMC; SNP, sodium nitroprusside; SOD, superoxide dismutase; TL, tibia length; Treg, T-regulatory lymphocytes; VSMC, vascular smooth muscle cells

Received 13 December, 2016

Revised 16 January, 2017

Accepted 6 February, 2017

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