Volume overload induces differential spatiotemporal regulation of myocardial soluble guanylyl cyclase in eccentric hypertrophy and heart failure

• Published in: Journal of molecular and cellular cardiology Vol. 60; pp. 72 - 83
• Main Authors: Liu, Yuchuan, Dillon, A. Ray, Tillson, Michael, Makarewich, Catherine, Nguyen, Vincent, Dell'Italia, Louis, Sabri, Abdel Karim, Rizzo, Victor, Tsai, Emily J
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.07.2013
• Subjects: Animals; Cardiomegaly - enzymology; Cardiomegaly - pathology; Cardiomegaly - physiopathology; Cardiovascular; Caveolae; Cell Adhesion Molecules - metabolism; Cyclic GMP - metabolism; Cyclic guanosine monophosphate signaling; Dogs; Eccentric hypertrophy; Female; Guanylate Cyclase - metabolism; Heart Failure - enzymology; Heart Failure - pathology; Heart Failure - physiopathology; Male; Membrane Microdomains - enzymology; Membrane Microdomains - pathology; Microfilament Proteins - metabolism; Mitral Valve Insufficiency - enzymology; Mitral Valve Insufficiency - pathology; Mitral Valve Insufficiency - physiopathology; Muscle Proteins - metabolism; Myocardium - enzymology; Myocardium - pathology; Nitric Oxide - metabolism; Oxidation-Reduction; Phosphoproteins - metabolism; Receptors, Cytoplasmic and Nuclear - metabolism; Signal Transduction; Soluble Guanylyl Cyclase; Time Factors; NO; cyclic guanosine monophosphate; left ventricle; LR; cGMP; LV; vasodilator-stimulated phosphoprotein; protein kinase G, cGMP-dependent protein kinase; sGC; PDE; caveolin-3 enriched lipid raft, caveolae; soluble guanylyl cyclase; NLR; RNS; ERK5; nitrated tyrosine; reactive nitrogen species; Eccentric hypertrophy; protein kinase C; protein kinase A, cAMP-dependent protein kinase; VASP; nitric oxide; Cav3; DEA/NO; Caveolae; MR; mitral regurgitation; Cyclic guanosine monophosphate signaling; PKA; Cav3 +LR; mitogen activated protein kinase; PKC; NO 2-Tyr; diethylammonium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate, diethylamine NONOate; MAPK; PKG; non-lipid raft; lipid raft; caveolin-3; phosphodiesterase; extracellular signal regulated kinase 5; Soluble guanylyl cyclase; Cav3+LR; NO2-Tyr
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2013.03.019

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 4 weeks and 12 months 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.