PPARγ Regulates Resistance Vessel Tone Through a Mechanism Involving RGS5-Mediated Control of PKC and BKCa Channel Activity
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 (SMC)-specific promoter. MA from transgenic mice exhibited a robust increase in myogenic tone. Patch clamp analysis revealed a reduced large conductance Ca2+-activated K+ (BKCa) current in freshly dissociated SMC from transgenic MA. Inhibition of protein kinase C (PKC) corrected both enhanced myogenic constriction and impaired BKCa 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. RGS5 siRNA caused augmented myogenic tone in intact mesenteric arteries and increased activation of PKC in SMC cultures. PPARγ; and PPAR δ; each bind to a PPAR response element close to the RGS5 promoter. RGS5 expression in non-transgenic MA was induced following 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 PKC, preserves BKCa channel activity, thus providing tight control of myogenic tone in the microcirculation.
- Blood vessels
- DNA microarray
- Peroxisome proliferator-activated receptor _
- Protein kinase C
- myogenic tone
- Received April 16, 2012.
- Accepted September 6, 2012.
- Copyright © 2012, American Heart Association