Pressure-overload-induced subcellular relocalization/oxidation of soluble guanylyl cyclase in the heart modulates enzyme stimulation

Emily J. Tsai, Yuchuan Liu, Norimichi Koitabashi, Djahida Bedja, Thomas Danner, Jean Francois Jasmin, Michael P. Lisanti, Andreas Friebe, Eiki Takimoto, David A. Kass

    Research output: Contribution to journalArticlepeer-review

    Abstract

    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. © 2012 American Heart Association, Inc.
    Original languageEnglish
    Pages (from-to)295-303
    Number of pages8
    JournalCirculation research
    Volume110
    Issue number2
    DOIs
    Publication statusPublished - 20 Jan 2012

    Keywords

    • cardiomyocyte
    • caveolae
    • hypertrophy
    • signaling
    • soluble guanylyl cyclase

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