title: Celastrol attenuates adipokine resistin-associated matrix interaction and migration of vascular smooth muscle cells.
abstract: Obesity instigates various health problems such as atherosclerosis, diabetes, and cancer. Resistin, an adipose tissue-specific secretory adipokine, operates endocrine functions through increasing insulin resistance. Vascular smooth muscle cells (SMC) migrate into the subendothelial space and proliferate, thereby contributing to neointimal formation in atherosclerosis and restenosis. The aim of this study was to elucidate whether celastrol obtained from Tripterygium wilfordii Hook, inhibited human aortic SMC migration. Celastrol capable of antagonizing inflammatory responses attenuated the resistin secretion from THP-1-derived macrophages. The macrophage-conditioned media promoted SMC proliferation and MMP-2 production, which was dampened by 10-100 nM celastrol. Celastrol encumbered the SMC migration in response to 50 ng/ml resistin, concomitant with the inhibition of induction of connective tissue growth factor and collagen I/IV. In addition, celastrol disabled human aortic SMC exposed to resistin from migrating. The resistin-induced shedding of integrin β2/β3 expression was demoted by celastrol, thereby contributing to the inhibition of collagen matrix-SMC interaction. Next, resistin-induced Toll-like receptor-4 (TLR-4) expression was abrogated by celastrol, indicating that TLR-4 was the resistin signaling receptor that was blocked by celastrol. Collectively, these results demonstrate that anti-inflammatory celastrol blunted the macrophage secretion of the adipokine resistin, and suppressed the SMC migration by disturbing the interaction between SMC and intimal collagen matrix. Therefore, celastrol may inhibit atherogenic migration of vascular SMC upon resistin loading by intimal macrophages within atherosclerotic lesions.
authors.affiliation: Department of Food and Nutrition, Hallym University, Chuncheon, Republic of Korea.
authors.forename: Sang-Wook
authors.initials: SW
authors.lastname: Kang
authors.forename: Min Soo
authors.initials: MS
authors.lastname: Kim
authors.forename: Hyun-Sung
authors.initials: HS
authors.lastname: Kim
authors.forename: Yunho
authors.initials: Y
authors.lastname: Kim
authors.forename: Daekeun
authors.initials: D
authors.lastname: Shin
authors.forename: Jung Han Yoon
authors.initials: JH
authors.lastname: Park
authors.forename: Young-Hee
authors.initials: YH
authors.lastname: Kang
mesh_terms: D001011:Aorta / Q000166:cytology / Q000187:drug effects; D050197:Atherosclerosis / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D008264:Macrophages / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D053978:Pentacyclic Triterpenes; D052243:Resistin / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D029757:Tripterygium; D014315:Triterpenes / Q000008:administration & dosage*
chemical_list: D024141:Collagen Type IV; D053978:Pentacyclic Triterpenes; D052243:Resistin; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014315:Triterpenes; C050414:celastrol