PPARγ Regulates Resistance Vessel Tone Through a Mechanism Involving RGS5-Mediated Control of Protein Kinase C and BKCa Channel Activity

Pimonrat KETSAWATSOMKRON; Ramón A LORCA; Henry L KEEN; Eric T WEATHERFORD; Xuebo Liu; Christopher J PELHAM; Justin L GROBE; Frank M FARACI; Sarah K ENGLAND; Curt D SIGMUND

doi:10.1161/CIRCRESAHA.112.271577

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PPARγ Regulates Resistance Vessel Tone Through a Mechanism Involving RGS5-Mediated Control of Protein Kinase C and BKCa Channel Activity

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PPARγ Regulates Resistance Vessel Tone Through a Mechanism Involving RGS5-Mediated Control of Protein Kinase C and BKCa Channel Activity

Pimonrat KETSAWATSOMKRON, Ramón A LORCA, Henry L KEEN, Eric T WEATHERFORD, Xuebo Liu, Christopher J PELHAM, Justin L GROBE, Frank M FARACI, Sarah K ENGLAND and Curt D SIGMUND

Circulation research, Vol.111(11), pp.1446-1458

2012

DOI: 10.1161/CIRCRESAHA.112.271577

PMID: 22962432

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https://doi.org/10.1161/CIRCRESAHA.112.271577View

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Abstract

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 Ca2+-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 Ca2+-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 Ca2+-activated K+ channel activity, thus providing tight control of myogenic tone in the microcirculation.

Fundamental and applied biological sciences. Psychology

Cardiology. Vascular system

Arterial hypertension. Arterial hypotension

Biological and medical sciences

Medical sciences

Vertebrates: cardiovascular system

Blood and lymphatic vessels

Details

Title: Subtitle: PPARγ Regulates Resistance Vessel Tone Through a Mechanism Involving RGS5-Mediated Control of Protein Kinase C and BKCa Channel Activity
Creators: Pimonrat KETSAWATSOMKRON - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, United States
Ramón A LORCA - Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, United States
Henry L KEEN - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, United States
Eric T WEATHERFORD - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, United States
Xuebo Liu - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, United States
Christopher J PELHAM - Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, United States
Justin L GROBE - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, United States
Frank M FARACI - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, United States
Sarah K ENGLAND - Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, United States
Curt D SIGMUND - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, United States
Resource Type: Journal article
Publication Details: Circulation research, Vol.111(11), pp.1446-1458
Publisher: Lippincott Williams & Wilkins; Hagerstown, MD
DOI: 10.1161/CIRCRESAHA.112.271577
PMID: 22962432
ISSN: 0009-7330
eISSN: 1524-4571
Language: English
Date published: 2012
Academic Unit: Molecular Physiology and Biophysics; Cardiovascular Medicine; Neuroscience and Pharmacology; Endocrinology and Metabolism; Internal Medicine; Iowa Institute of Human Genetics
Record Identifier: 9984040491202771

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