Document Detail


NO triggers RGS4 degradation to coordinate angiogenesis and cardiomyocyte growth.
MedLine Citation:
PMID:  23454748     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Myocardial hypertrophy is an adaptation to increased hemodynamic demands. An increase in heart tissue must be matched by a corresponding expansion of the coronary vasculature to maintain and adequate supply of oxygen and nutrients for the heart. The physiological mechanisms that underlie the coordination of angiogenesis and cardiomyocyte growth are unknown. We report that induction of myocardial angiogenesis promotes cardiomyocyte growth and cardiac hypertrophy through a novel NO-dependent mechanism. We used transgenic, conditional overexpression of placental growth factor (PlGF) in murine cardiac tissues to stimulate myocardial angiogenesis and increase endothelial-derived NO release. NO production, in turn, induced myocardial hypertrophy by promoting proteasomal degradation of regulator of G protein signaling type 4 (RGS4), thus relieving the repression of the Gβγ/PI3Kγ/AKT/mTORC1 pathway that stimulates cardiomyocyte growth. This hypertrophic response was prevented by concomitant transgenic expression of RGS4 in cardiomyocytes. NOS inhibitor L-NAME also significantly attenuated RGS4 degradation, and reduced activation of AKT/mTORC1 signaling and induction of myocardial hypertrophy in PlGF transgenic mice, while conditional cardiac-specific PlGF expression in eNOS knockout mice did not induce myocardial hypertrophy. These findings describe a novel NO/RGS4/Gβγ/PI3Kγ/AKT mechanism that couples cardiac vessel growth with myocyte growth and heart size.
Authors:
Irina M Jaba; Zhen W Zhuang; Na Li; Yifeng Jiang; Kathleen A Martin; Albert J Sinusas; Xenophon Papademetris; Michael Simons; William C Sessa; Lawrence H Young; Daniela Tirziu
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  123     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-05-09     Completed Date:  2013-05-20     Revised Date:  2013-09-30    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1718-31     Citation Subset:  AIM; IM    
Affiliation:
Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut 06510, USA.
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MeSH Terms
Descriptor/Qualifier:
Adaptation, Biological
Animals
Cell Enlargement*
Cells, Cultured
Coronary Vessels / physiology
Endothelium, Vascular / metabolism,  physiology
Heart Ventricles / cytology,  metabolism
Mice
Mice, Inbred C57BL
Mice, Transgenic
Myocytes, Cardiac / drug effects,  physiology*
NG-Nitroarginine Methyl Ester / pharmacology
Neovascularization, Physiologic*
Nitric Oxide / physiology*
Nitric Oxide Synthase / antagonists & inhibitors,  metabolism
Pregnancy Proteins / physiology
Proteins / metabolism
Proteolysis
Proto-Oncogene Proteins c-akt / metabolism
RGS Proteins / metabolism*
Rats
Rats, Sprague-Dawley
Signal Transduction
Chemical
Reg. No./Substance:
0/Pregnancy Proteins; 0/Proteins; 0/RGS Proteins; 0/mechanistic target of rapamycin complex 1; 10102-43-9/Nitric Oxide; 144589-93-5/placenta growth factor; 175335-35-0/RGS4 protein; 50903-99-6/NG-Nitroarginine Methyl Ester; EC 1.14.13.39/Nitric Oxide Synthase; EC 2.7.11.1/Proto-Oncogene Proteins c-akt
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