| Pressure-Overload-Induced Subcellular Relocalization/Oxidation of Soluble Guanylate Cyclase in the Heart Modulates Enzyme Stimulation. | |
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MedLine Citation:
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PMID: 22095726 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Rationale:Soluble guanylyl cyclase (sGC) generates cyclic guanosine monophophate (cGMP) on 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. |
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Authors:
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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:
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Type: JOURNAL ARTICLE Date: 2011-11-17 |
Journal Detail:
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Title: Circulation research Volume: - ISSN: 1524-4571 ISO Abbreviation: - Publication Date: 2011 Nov |
Date Detail:
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Created Date: 2011-11-18 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0047103 Medline TA: Circ Res Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Section in Cardiology, Department of Medicine, Temple University School of Medicine, Philadelphia, PA. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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