PPARγ regulates resistance vessel tone through a mechanism involving RGS5-mediated control of protein kinase C and BKCa channel activity. Circ Res 2012 Nov 09;111(11):1446-58
Date
09/11/2012Pubmed ID
22962432Pubmed Central ID
PMC3494760DOI
10.1161/CIRCRESAHA.112.271577Scopus ID
2-s2.0-84870039725 (requires institutional sign-in at Scopus site) 53 CitationsAbstract
RATIONALE: 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.
METHODS AND 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.
Author List
Ketsawatsomkron P, Lorca RA, Keen HL, Weatherford ET, Liu X, Pelham CJ, Grobe JL, Faraci FM, England SK, Sigmund CDAuthors
Justin L. Grobe PhD Professor in the Physiology department at Medical College of WisconsinCurt Sigmund PhD Chair, Professor in the Physiology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Angiotensin IIAnimals
Blotting, Western
Female
Gene Expression Profiling
Large-Conductance Calcium-Activated Potassium Channel alpha Subunits
Male
Mesenteric Arteries
Mice
Mice, Inbred C57BL
Mice, Transgenic
Muscle, Smooth, Vascular
Mutation
Myocytes, Smooth Muscle
Naphthalenes
PPAR gamma
Patch-Clamp Techniques
Potassium Channel Blockers
Protein Kinase C
RGS Proteins
RNA Interference
Reverse Transcriptase Polymerase Chain Reaction
Tetraethylammonium
Vasoconstriction
Vasoconstrictor Agents
