title: Regulation of peroxisome proliferator-activated receptor-γ by angiotensin II via transforming growth factor-β1-activated p38 mitogen-activated protein kinase in aortic smooth muscle cells.
abstract: OBJECTIVE
  Peroxisome proliferator-activated receptor-γ (PPARγ) ligands attenuate angiotensin II (Ang II)-induced atherosclerosis through interactions with vascular smooth muscle cell (VSMC)-specific PPARγ in hypercholesterolemic mice. Therefore, the purpose of this study was to determine the mechanism of Ang II-mediated intracellular regulation of PPARγ in VSMCs.
  
  
  RESULTS
  Incubation of cultured mouse aortic VSMCs with Ang II for 24 hours reduced abundance of PPARγ protein, mRNA, and transcriptional activity (P<0.001). This effect was attenuated by an angiotensin type 1 receptor antagonist, losartan. Ang II-induced PPARγ reduction was dependent on stimulation of transforming growth factor (TGF)-β1 as demonstrated using either a neutralizing antibody or small interfering RNA (siRNA). Ang II-induced TGF-β1 secretion was dependent on epidermal growth factor receptor kinase activation through reactive oxygen species production. Inhibition of p38 mitogen-activated protein kinase by SB203580 or siRNA inhibited both Ang II- and TGF-β1-induced PPARγ reduction. Blockade of TGF-β1 decreased p38 phosphorylation induced by Ang II. siRNA-mediated inhibition of histone deacetylase 3 attenuated p38-mediated reductions in PPARγ abundance.
  
  
  CONCLUSIONS
  These findings suggest that Ang II decreases PPARγ abundance in cultured VSMCs via an angiotensin type 1 receptor-dependent secretion of TGF-β1 via phosphorylation of p38 mitogen-activated protein kinase and histone deacetylase 3.
authors.affiliation: Saha Cardiovascular Research Center, BBSRB, Rm B249, University of Kentucky, Lexington, KY 40536-0509, USA. venkat.subramanian@uky.edu
authors.forename: Venkateswaran
authors.initials: V
authors.lastname: Subramanian
authors.forename: Jonathan
authors.initials: J
authors.lastname: Golledge
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Heywood
authors.forename: Dennis
authors.initials: D
authors.lastname: Bruemmer
authors.forename: Alan
authors.initials: A
authors.lastname: Daugherty
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000187:drug effects / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000099186:Histone Deacetylase 3
chemical_list: D000804:Angiotensin II; D047228:Angiotensin II Type 1 Receptor Blockers; D004791:Enzyme Inhibitors; D006655:Histone Deacetylases; D007093:Imidazoles; D019808:Losartan; D047495:PPAR gamma; D011725:Pyridines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D044140:Receptor, Angiotensin, Type 1; D053773:Transforming Growth Factor beta1; D048051:p38 Mitogen-Activated Protein Kinases; D000099186:Histone Deacetylase 3; C093642:SB 203580
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