title: Volume overload induces differential spatiotemporal regulation of myocardial soluble guanylyl cyclase in eccentric hypertrophy and heart failure.
abstract: Nitric oxide activation of soluble guanylyl cyclase (sGC) blunts the cardiac stress response, including cardiomyocyte hypertrophy. In the concentric hypertrophied heart, oxidation and re-localization of myocardial sGC diminish cyclase activity, thus aggravating depressed nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signaling in the pressure-overloaded failing heart. Here, we hypothesized that volume-overload differentially disrupts myocardial sGC activity during early compensated and late decompensated stages of eccentric hypertrophy. To this end, we studied the expression, redox state, subcellular localization, and activity of sGC in the left ventricle of dogs subjected to chordal rupture-induced mitral regurgitation (MR). Unoperated dogs were used as Controls. Animals were studied at 4weeks and 12months post chordal rupture, corresponding with early (4wkMR) and late stages (12moMR) of eccentric hypertrophy. We found that the sGC heterodimer subunits relocalized away from caveolae-enriched lipid raft microdomains at different stages; sGCβ1 at 4wkMR, followed by sGCα1 at 12moMR. Moreover, expression of both sGC subunits fell at 12moMR. Using the heme-dependent NO donor DEA/NO and NO-/heme-independent sGC activator BAY 60-2770, we determined the redox state and inducible activity of sGC in the myocardium, within caveolae and non-lipid raft microdomains. sGC was oxidized in non-lipid raft microdomains at 4wkMR and 12moMR. While overall DEA/NO-responsiveness remained intact in MR hearts, DEA/NO responsiveness of sGC in non-lipid raft microdomains was depressed at 12moMR. Caveolae-localization protected sGC against oxidation. Further studies revealed that these modifications of sGC were also reflected in caveolae-localized cGMP-dependent protein kinase (PKG) and MAPK signaling. In MR hearts, PKG-mediated phosphorylation of vasodilator-stimulated phosphoprotein (VASP) disappeared from caveolae whereas caveolae-localization of phosphorylated ERK5 increased. These findings show that differential oxidation, re-localization, and expression of sGC subunits distinguish eccentric from concentric hypertrophy as well as compensated from decompensated heart failure.
authors.affiliation: Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Yuchuan
authors.initials: Y
authors.lastname: Liu
authors.forename: A Ray
authors.initials: AR
authors.lastname: Dillon
authors.forename: Michael
authors.initials: M
authors.lastname: Tillson
authors.forename: Catherine
authors.initials: C
authors.lastname: Makarewich
authors.forename: Vincent
authors.initials: V
authors.lastname: Nguyen
authors.forename: Louis
authors.initials: L
authors.lastname: Dell'Italia
authors.forename: Abdel Karim
authors.initials: AK
authors.lastname: Sabri
authors.forename: Victor
authors.initials: V
authors.lastname: Rizzo
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Tsai
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004285:Dogs; D005260:Female; D006162:Guanylate Cyclase / Q000378:metabolism*; D006333:Heart Failure / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D021962:Membrane Microdomains / Q000201:enzymology / Q000473:pathology; D008840:Microfilament Proteins / Q000378:metabolism; D008944:Mitral Valve Insufficiency / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D009124:Muscle Proteins / Q000378:metabolism*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D010084:Oxidation-Reduction; D010750:Phosphoproteins / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction; D000071756:Soluble Guanylyl Cyclase; D013997:Time Factors; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D009124:Muscle Proteins; D010750:Phosphoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D000098662:Vasodilator-Stimulated Phosphoprotein; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP