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Circ Res. 2012 Jan 20;110(2):295-303. doi: 10.1161/CIRCRESAHA.111.259242. Epub 2011 Nov 17.

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

Author information

1
Division of Cardiology, Johns Hopkins Medical Institutions, 720 Rutland Ave, Ross 858, Baltimore, MD 21205, USA. emily.tsai@tuhs.temple.edu

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.

PMID:
22095726
PMCID:
PMC4264382
DOI:
10.1161/CIRCRESAHA.111.259242
[Indexed for MEDLINE]
Free PMC Article

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