Journal article
Conditional deletion of smooth muscle Cullin-3 causes severe progressive hypertension
JCI insight, Vol.4(14), e129793
07/25/2019
DOI: 10.1172/jci.insight.129793
PMCID: PMC6675584
PMID: 31184598
Abstract
Patients with mutations in Cullin-3 (
CUL3
) exhibit severe early-onset hypertension, but the contribution of the smooth muscle remains unclear. Conditional genetic ablation of CUL3 in vascular smooth muscle (S-CUL3KO) causes progressive impairment in response to NO, rapid development of severe hypertension, and increased arterial stiffness. Loss of CUL3 in primary aortic smooth muscle cells or aorta resulted in decreased expression of the NO receptor soluble guanylate cyclase (sGC), a marked reduction in cGMP production, and impaired vasodilation to cGMP analogs. Vasodilation responses to a selective large-conductance Ca
2+
-activated K
+
channel activator were normal, suggesting that downstream signals that promote smooth muscle–dependent relaxation remained intact. We conclude that smooth muscle–specific CUL3 ablation impairs both cGMP production and cGMP responses and that loss of CUL3 function selectively in smooth muscle is sufficient to cause severe hypertension by interfering with the NO/sGC/cGMP pathway. Our study provides evidence that vascular smooth muscle CUL3 is a major regulator of BP. CUL3 mutations cause severe vascular dysfunction, arterial stiffness, and hypertension due to defects in vascular smooth muscle.
Smooth muscle-specific Cullin-3 ablation impairs cGMP production and action and causes severe hypertension by interfering with the NO-sGC-cGMP pathway.
Details
- Title: Subtitle
- Conditional deletion of smooth muscle Cullin-3 causes severe progressive hypertension
- Creators
- Larry N Agbor - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAAnand R Nair - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAJing Wu - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAKo-Ting Lu - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USADeborah R Davis - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAHenry L Keen - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAFrederick W Quelle - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAJames A McCormick - Division of Nephrology & Hypertension, Department of Medicine, Oregon Health & Science University, Portland, Oregon, USAJeffrey D Singer - Department of Biology, Portland State University, Portland, Oregon, USACurt D Sigmund - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.4(14), e129793
- Publisher
- American Society for Clinical Investigation
- DOI
- 10.1172/jci.insight.129793
- PMID
- 31184598
- PMCID
- PMC6675584
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Grant note
- R01 HL125603 / ; P01 HL084207 / ; T32 HL007121 / ; R01 DK098141 / ; R01 HL131689 / ; 15SFRN23480000 / ; Unnumbered / ; R35 HL144807 / ; 17POST33660685 / ;
- Language
- English
- Date published
- 07/25/2019
- Academic Unit
- Molecular Physiology and Biophysics; Pathology; Neuroscience and Pharmacology; Internal Medicine; Iowa Institute of Human Genetics
- Record Identifier
- 9984040349902771
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