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 journalArticle

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.

Original languageEnglish (US)
Pages (from-to)295-303
Number of pages9
JournalCirculation Research
Volume110
Issue number2
DOIs
StatePublished - Jan 20 2012

Fingerprint

Pressure
Nitric Oxide
Enzymes
Constriction
Heme
Guanosine
Soluble Guanylyl Cyclase
Membrane Microdomains
Caveolins
Cardiomegaly
Inbred C57BL Mouse
Hypertrophy
Hydrolysis
Lipids

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Pressure-overload-induced subcellular relocalization/oxidation of soluble guanylyl cyclase in the heart modulates enzyme stimulation. / Tsai, Emily J.; Liu, Yuchuan; Koitabashi, Norimichi; Bedja, Djahida; Danner, Thomas; Jasmin, Jean Francois; Lisanti, Michael P.; Friebe, Andreas; Takimoto, Eiki; Kass, David A.

In: Circulation Research, Vol. 110, No. 2, 20.01.2012, p. 295-303.

Research output: Contribution to journalArticle

Tsai, EJ, Liu, Y, Koitabashi, N, Bedja, D, Danner, T, Jasmin, JF, Lisanti, MP, Friebe, A, Takimoto, E & Kass, DA 2012, 'Pressure-overload-induced subcellular relocalization/oxidation of soluble guanylyl cyclase in the heart modulates enzyme stimulation', Circulation Research, vol. 110, no. 2, pp. 295-303. https://doi.org/10.1161/CIRCRESAHA.111.259242
Tsai, Emily J. ; Liu, Yuchuan ; Koitabashi, Norimichi ; Bedja, Djahida ; Danner, Thomas ; Jasmin, Jean Francois ; Lisanti, Michael P. ; Friebe, Andreas ; Takimoto, Eiki ; Kass, David A. / Pressure-overload-induced subcellular relocalization/oxidation of soluble guanylyl cyclase in the heart modulates enzyme stimulation. In: Circulation Research. 2012 ; Vol. 110, No. 2. pp. 295-303.
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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.",
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author = "Tsai, {Emily J.} and Yuchuan Liu and Norimichi Koitabashi and Djahida Bedja and Thomas Danner and Jasmin, {Jean Francois} and Lisanti, {Michael P.} and Andreas Friebe and Eiki Takimoto and Kass, {David A}",
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T1 - Pressure-overload-induced subcellular relocalization/oxidation of soluble guanylyl cyclase in the heart modulates enzyme stimulation

AU - Tsai, Emily J.

AU - Liu, Yuchuan

AU - Koitabashi, Norimichi

AU - Bedja, Djahida

AU - Danner, Thomas

AU - Jasmin, Jean Francois

AU - Lisanti, Michael P.

AU - Friebe, Andreas

AU - Takimoto, Eiki

AU - Kass, David A

PY - 2012/1/20

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N2 - 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.

AB - 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.

KW - cardiomyocyte

KW - caveolae

KW - hypertrophy

KW - signaling

KW - soluble guanylyl cyclase

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