Document Detail


Regulator of G-protein signaling 5 controls blood pressure homeostasis and vessel wall remodeling.
MedLine Citation:
PMID:  23303165     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
RATIONALE: Regulator of G-protein signaling 5 (RGS5) modulates G-protein-coupled receptor signaling and is prominently expressed in arterial smooth muscle cells. Our group first reported that RGS5 is important in vascular remodeling during tumor angiogenesis. We hypothesized that RGS5 may play an important role in vessel wall remodeling and blood pressure regulation.
OBJECTIVE: To demonstrate that RGS5 has a unique and nonredundant role in the pathogenesis of hypertension and to identify crucial RGS5-regulated signaling pathways.
METHODS AND RESULTS: We observed that arterial RGS5 expression is downregulated with chronically elevated blood pressure after angiotensin II infusion. Using a knockout mouse model, radiotelemetry, and pharmacological inhibition, we subsequently showed that loss of RGS5 results in profound hypertension. RGS5 signaling is linked to the renin-angiotensin system and directly controls vascular resistance, vessel contractility, and remodeling. RGS5 deficiency aggravates pathophysiological features of hypertension, such as medial hypertrophy and fibrosis. Moreover, we demonstrate that protein kinase C, mitogen-activated protein kinase/extracellular signal-regulated kinase, and Rho kinase signaling pathways are major effectors of RGS5-mediated hypertension.
CONCLUSIONS: Loss of RGS5 results in hypertension. Loss of RGS5 signaling also correlates with hyper-responsiveness to vasoconstrictors and vascular stiffening. This establishes a significant, distinct, and causal role of RGS5 in vascular homeostasis. RGS5 modulates signaling through the angiotensin II receptor 1 and major Gαq-coupled downstream pathways, including Rho kinase. So far, activation of RhoA/Rho kinase has not been associated with RGS molecules. Thus, RGS5 is a crucial regulator of blood pressure homeostasis with significant clinical implications for vascular pathologies, such as hypertension.
Authors:
Vasyl Holobotovskyy; Mitali Manzur; Marianne Tare; Jennifer Burchell; Erin Bolitho; Helena Viola; Livia C Hool; Leonard F Arnolda; Douglas J McKitrick; Ruth Ganss
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-01-09
Journal Detail:
Title:  Circulation research     Volume:  112     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-01     Completed Date:  2013-06-25     Revised Date:  2014-07-31    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  781-91     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Blood Pressure / physiology*
Blood Vessels / physiology*
Disease Models, Animal
Female
Homeostasis / physiology*
Hypertension / physiopathology
MAP Kinase Signaling System / physiology
Male
Mice
Mice, Knockout
Muscle, Smooth, Vascular / physiology*
Protein Kinase C / physiology
RGS Proteins / deficiency,  genetics,  physiology*
Signal Transduction / physiology
Vasoconstriction / physiology
rho-Associated Kinases / physiology
Chemical
Reg. No./Substance:
0/RGS Proteins; 0/Rgs5 protein, mouse; EC 2.7.11.1/rho-Associated Kinases; EC 2.7.11.13/Protein Kinase C

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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