Journal article
RhoBTB1 protects against hypertension and arterial stiffness by restraining phosphodiesterase 5 activity
The Journal of clinical investigation, Vol.129(6), pp.2318-2332
03/21/2019
DOI: 10.1172/JCI123462
PMCID: PMC6546477
PMID: 30896450
Abstract
Mice selectively expressing a PPARγ dominant-negative mutation in vascular smooth muscle exhibit RhoBTB1 deficiency and hypertension. Our rationale was to use genetic complementation to uncover the mechanism of action of RhoBTB1 in vascular smooth muscle. Inducible smooth muscle–specific restoration of RhoBTB1 fully corrected hypertension and arterial stiffness by improving vasodilator function. Notably, the cardiovascular protection occurred despite the preservation of increased agonist-mediated contraction and RhoA and Rho kinase activity, suggesting that RhoBTB1 selectively controls vasodilation. RhoBTB1 augmented the cyclic 3′,5′-monophosphate (cGMP) response to NO by restraining the activity of phosphodiesterase 5 (PDE5) through its action as a substrate adaptor delivering PDE5 to the Cullin-3 E3 ring ubiquitin ligase complex for ubiquitination, thereby inhibiting PDE5. Angiotensin II infusion also caused RhoBTB1 deficiency and hypertension, which were prevented by smooth muscle–specific RhoBTB1 restoration. We conclude that RhoBTB1 protected against hypertension, vascular smooth muscle dysfunction, and arterial stiffness in at least 2 models of hypertension.
Details
- Title: Subtitle
- RhoBTB1 protects against hypertension and arterial stiffness by restraining phosphodiesterase 5 activity
- Creators
- Masashi Mukohda - Department of Pharmacology, UIHC Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAShi Fang - Department of Pharmacology, UIHC Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAJing Wu - Department of Pharmacology, UIHC Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USALarry N Agbor - Department of Pharmacology, UIHC Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAAnand R Nair - Department of Pharmacology, UIHC Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAStella-Rita C Ibeawuchi - Department of Pharmacology, UIHC Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAChunyan Hu - Department of Pharmacology, UIHC Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAXuebo Liu - Department of Pharmacology, UIHC Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAKo-Ting Lu - Department of Pharmacology, UIHC Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USADeng-Fu Guo - Department of Pharmacology, UIHC Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USADeborah R Davis - Department of Pharmacology, UIHC Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAHenry L Keen - Department of Pharmacology, UIHC Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAFrederick W Quelle - Department of Pharmacology, UIHC Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USACurt D Sigmund - Department of Pharmacology, UIHC Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.129(6), pp.2318-2332
- Publisher
- American Society for Clinical Investigation
- DOI
- 10.1172/JCI123462
- PMID
- 30896450
- PMCID
- PMC6546477
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Grant note
- Sigmund / ; HL131689 / ; 15SFRN23480000 / ; HL084207 / ; HL125603 / ; HL144807 / ; 17POST33660685 / ;
- Language
- English
- Date published
- 03/21/2019
- Academic Unit
- Molecular Physiology and Biophysics; Pathology; Neuroscience and Pharmacology; Internal Medicine; Iowa Institute of Human Genetics
- Record Identifier
- 9984040231102771
Metrics
26 Record Views