Document Detail


Pressure-overload-induced subcellular relocalization/oxidation of soluble guanylyl cyclase in the heart modulates enzyme stimulation.
MedLine Citation:
PMID:  22095726     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
RATIONALE: Soluble guanylyl cyclase (sGC) generates cyclic guanosine monophophate (cGMP) upon activation by nitric oxide (NO). Cardiac NO-sGC-cGMP signaling blunts cardiac stress responses, including pressure-overload-induced hypertrophy. The latter itself depresses signaling through this pathway by reducing NO generation and enhancing cGMP hydrolysis.
OBJECTIVE: We tested the hypothesis that the sGC response to NO also declines with pressure-overload stress and assessed the role of heme-oxidation and altered intracellular compartmentation of sGC as potential mechanisms.
METHODS AND RESULTS: C57BL/6 mice subjected to transverse aortic constriction (TAC) developed cardiac hypertrophy and dysfunction. NO-stimulated sGC activity was markedly depressed, whereas NO- and heme-independent sGC activation by BAY 60-2770 was preserved. Total sGCα(1) and β(1) expression were unchanged by TAC; however, sGCβ(1) subunits shifted out of caveolin-enriched microdomains. NO-stimulated sGC activity was 2- to 3-fold greater in Cav3-containing lipid raft versus nonlipid raft domains in control and 6-fold greater after TAC. In contrast, BAY 60-2770 responses were >10 fold higher in non-Cav3 domains with and without TAC, declining about 60% after TAC within each compartment. Mice genetically lacking Cav3 had reduced NO- and BAY-stimulated sGC activity in microdomains containing Cav3 for controls but no change within non-Cav3-enriched domains.
CONCLUSIONS: Pressure overload depresses NO/heme-dependent sGC activation in the heart, consistent with enhanced oxidation. The data reveal a novel additional mechanism for reduced NO-coupled sGC activity related to dynamic shifts in membrane microdomain localization, with Cav3-microdomains protecting sGC from heme-oxidation and facilitating NO responsiveness. Translocation of sGC out of this domain favors sGC oxidation and contributes to depressed NO-stimulated sGC activity.
Authors:
Emily J Tsai; Yuchuan Liu; Norimichi Koitabashi; Djahida Bedja; Thomas Danner; Jean-Francois Jasmin; Michael P Lisanti; Andreas Friebe; Eiki Takimoto; David A Kass
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-11-17
Journal Detail:
Title:  Circulation research     Volume:  110     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2012 Jan 
Date Detail:
Created Date:  2012-01-23     Completed Date:  2012-03-06     Revised Date:  2013-02-15    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  295-303     Citation Subset:  IM    
Affiliation:
Division of Cardiology, Johns Hopkins Medical Institutions, 720 Rutland Ave, Ross 858, Baltimore, MD 21205, USA. emily.tsai@tuhs.temple.edu
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MeSH Terms
Descriptor/Qualifier:
Animals
Benzoates / pharmacology
Biphenyl Compounds
Cardiomegaly / enzymology*,  pathology,  physiopathology
Caveolin 3 / genetics,  metabolism
Cyclic GMP / metabolism
Disease Models, Animal
Down-Regulation
Enzyme Activation
Enzyme Activators / pharmacology
Guanylate Cyclase / metabolism*
Heme / metabolism
Hydrocarbons, Fluorinated / pharmacology
Hydrolysis
Membrane Microdomains / drug effects,  enzymology*,  pathology
Mice
Mice, Inbred C57BL
Mice, Knockout
Myocytes, Cardiac / drug effects,  enzymology*,  pathology
Nitric Oxide / metabolism
Oxidation-Reduction
Protein Transport
Receptors, Cytoplasmic and Nuclear / metabolism*
Signal Transduction
Grant Support
ID/Acronym/Agency:
HL-089297/HL/NHLBI NIH HHS; HL-093432/HL/NHLBI NIH HHS; HL093432/HL/NHLBI NIH HHS; R01 HL093432/HL/NHLBI NIH HHS; R01 HL093432-04/HL/NHLBI NIH HHS; T32-HL007227/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/4-(((4-carboxybutyl) (2- (5-fluoro-2-((4'-(trifluoromethyl) biphenyl-4-yl)methoxy)phenyl)ethyl) amino)methyl)benzoic acid; 0/Benzoates; 0/Biphenyl Compounds; 0/Cav3 protein, mouse; 0/Caveolin 3; 0/Enzyme Activators; 0/Hydrocarbons, Fluorinated; 0/Receptors, Cytoplasmic and Nuclear; 10102-43-9/Nitric Oxide; 14875-96-8/Heme; 7665-99-8/Cyclic GMP; EC 4.6.1.2/Guanylate Cyclase; EC 4.6.1.2/soluble guanylyl cyclase

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


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