title: PPARγ regulates resistance vessel tone through a mechanism involving RGS5-mediated control of protein kinase C and BKCa channel activity.
abstract: BACKGROUND
  Activation of peroxisome proliferator-activated receptor-γ (PPARγ) by thiazolidinediones lowers blood pressure, whereas PPARγ mutations cause hypertension. Previous studies suggest these effects may be mediated through the vasculature, but the underlying mechanisms remain unclear.
  
  
  OBJECTIVE
  To identify PPARγ mechanisms and transcriptional targets in vascular smooth muscle and their role in regulating resistance artery tone.
  
  
  RESULTS
  We studied mesenteric artery (MA) from transgenic mice expressing dominant-negative (DN) mutant PPARγ driven by a smooth muscle cell-specific promoter. MA from transgenic mice exhibited a robust increase in myogenic tone. Patch clamp analysis revealed a reduced large conductance Ca(2+)-activated K(+) (BKCa) current in freshly dissociated smooth muscle cell from transgenic MA. Inhibition of protein kinase C corrected both enhanced myogenic constriction and impaired the large conductance Ca(2+)-activated K(+) channel function. Gene expression profiling revealed a marked loss of the regulator of G protein signaling 5 (RGS5) mRNA in transgenic MA, which was accompanied by a substantial increase in angiotensin II-induced constriction in MA. Small interfering RNA targeting RGS5 caused augmented myogenic tone in intact mesenteric arteries and increased activation of protein kinase C in smooth muscle cell cultures. PPARγ and PPARδ each bind to a PPAR response element close to the RGS5 promoter. RGS5 expression in nontransgenic MA was induced after activation of either PPARγ or PPARδ, an effect that was markedly blunted by DN PPARγ.
  
  
  CONCLUSIONS
  We conclude that RGS5 in smooth muscle is a PPARγ and PPARδ target, which when activated blunts angiotensin II-mediated activation of protein kinase C, and preserves the large conductance Ca(2+)-activated K(+) channel activity, thus providing tight control of myogenic tone in the microcirculation.
authors.affiliation: Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Pimonrat
authors.initials: P
authors.lastname: Ketsawatsomkron
authors.forename: Ramón A
authors.initials: RA
authors.lastname: Lorca
authors.forename: Henry L
authors.initials: HL
authors.lastname: Keen
authors.forename: Eric T
authors.initials: ET
authors.lastname: Weatherford
authors.forename: Xuebo
authors.initials: X
authors.lastname: Liu
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Pelham
authors.forename: Justin L
authors.initials: JL
authors.lastname: Grobe
authors.forename: Frank M
authors.initials: FM
authors.lastname: Faraci
authors.forename: Sarah K
authors.initials: SK
authors.lastname: England
authors.forename: Curt D
authors.initials: CD
authors.lastname: Sigmund
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D005260:Female; D020869:Gene Expression Profiling; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008638:Mesenteric Arteries / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009154:Mutation; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019789:Tetraethylammonium / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: C530995:BKCa protein, mouse; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D009281:Naphthalenes; D047495:PPAR gamma; D026902:Potassium Channel Blockers; D020710:RGS Proteins; C105346:Rgs5 protein, mouse; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D019789:Tetraethylammonium; D011493:Protein Kinase C; C058819:calphostin C