PPAR? regulates resistance vessel tone through a mechanism involving RGS5-mediated control of protein kinase C and BKCa channel activity.

ABSTRACT: Activation of peroxisome proliferator-activated receptor-? (PPAR?) by thiazolidinediones lowers blood pressure, whereas PPAR? mutations cause hypertension. Previous studies suggest these effects may be mediated through the vasculature, but the underlying mechanisms remain unclear.To identify PPAR? mechanisms and transcriptional targets in vascular smooth muscle and their role in regulating resistance artery tone.We studied mesenteric artery (MA) from transgenic mice expressing dominant-negative (DN) mutant PPAR? 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. PPAR? and PPAR? each bind to a PPAR response element close to the RGS5 promoter. RGS5 expression in nontransgenic MA was induced after activation of either PPAR? or PPAR?, an effect that was markedly blunted by DN PPAR?.We conclude that RGS5 in smooth muscle is a PPAR? and PPAR? 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.

SUBMITTER: Ketsawatsomkron P 

PROVIDER: S-EPMC3494760 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature