Institutional members access full text with Ovid®

Share this article on:

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: ernesto.schiffrin@mcgill.ca

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

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.jhypertension.com).

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.