title: Pressure-overload-induced subcellular relocalization/oxidation of soluble guanylyl cyclase in the heart modulates enzyme stimulation.
abstract: BACKGROUND
  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.
  
  
  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.affiliation: Division of Cardiology, Johns Hopkins Medical Institutions, 720 Rutland Ave, Ross 858, Baltimore, MD 21205, USA. emily.tsai@tuhs.temple.edu
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Tsai
authors.forename: Yuchuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Norimichi
authors.initials: N
authors.lastname: Koitabashi
authors.forename: Djahida
authors.initials: D
authors.lastname: Bedja
authors.forename: Thomas
authors.initials: T
authors.lastname: Danner
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Jasmin
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
authors.forename: Andreas
authors.initials: A
authors.lastname: Friebe
authors.forename: Eiki
authors.initials: E
authors.lastname: Takimoto
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001713:Biphenyl Compounds; D006332:Cardiomegaly / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D051244:Caveolin 3 / Q000235:genetics / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000378:metabolism*; D006418:Heme / Q000378:metabolism; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D006868:Hydrolysis; D021962:Membrane Microdomains / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D010084:Oxidation-Reduction; D021381:Protein Transport; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction; D000071756:Soluble Guanylyl Cyclase
chemical_list: C528797:4-(((4-carboxybutyl) (2- (5-fluoro-2-((4'-(trifluoromethyl) biphenyl-4-yl)methoxy)phenyl)ethyl) amino)methyl)benzoic acid; D001565:Benzoates; D001713:Biphenyl Compounds; C495548:Cav3 protein, mouse; D051244:Caveolin 3; D020536:Enzyme Activators; D006845:Hydrocarbons, Fluorinated; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D006418:Heme; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP
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