Rosiglitazone attenuates endothelin-1-induced vasoconstriction by upregulating endothelial expression of endothelin B receptor.
Thiazolidinediones improve insulin resistance and endothelial dysfunction. However, the mechanisms underlying the vasoprotective effects of thiazolidinediones remain to be fully elucidated. The present study aimed to examine the molecular mechanism for the anti-vasoconstrictive effects of rosiglitazone in response to endothelin (ET) 1. Mouse aortas were treated with rosiglitazone for 24 hours, and ET-1-induced vasoconstriction was assessed by wire myography. The results showed that rosiglitazone attenuated ET-1-induced contraction in mouse aortas; this effect was abolished by ET-B receptor (ET(B)R) antagonist, NO synthase inhibitor, and by the removal of endothelium. By using Northern blotting, real-time RT-PCR, Western blotting, and immunohistochemical techniques, we found that rosiglitazone upregulated expression of ET(B)R at both mRNA and protein levels in mouse aortas and human vascular endothelial cells. The induction of ET(B)R was prevented by peroxisome proliferator-activated receptor-gamma antagonism. Luciferase reporter assay showed that rosiglitazone enhanced ET(B)R gene promoter activity. Furthermore, chromatin immunoprecipitation assays demonstrated that peroxisome proliferator-activated receptor-gamma can directly bind to ET(B)R gene promoter. Furthermore, in vivo treatment with rosiglitazone also attenuated the ET-1-induced vasoconstrictions and increased the ET(B)R expression in mouse aortas and mesenteric arteries. In conclusion, these results demonstrate that rosiglitazone attenuated ET-1-induced vasoconstriction through the upregulation of endothelial ET(B)R, which is a peroxisome proliferator-activated receptor-gamma direct target.
Tian
Jianwei
J
Institute of Cardiovascular Science and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing, China.
Wong
Wing Tak
WT
Tian
Xiao Yu
XY
Zhang
Peng
P
Huang
Yu
Y
Wang
Nanping
N
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D005786:Gene Expression Regulation; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007150:Immunohistochemistry; D007333:Insulin Resistance / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012313:RNA / Q000235:genetics*; D044023:Receptor, Endothelin B / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents
D019332:Endothelin-1; D007004:Hypoglycemic Agents; D044023:Receptor, Endothelin B; D045162:Thiazolidinediones; D014665:Vasodilator Agents; D000077154:Rosiglitazone; D012313:RNA