cGMP-dependent protein kinase contributes to hydrogen sulfide-stimulated vasorelaxation.
Mariarosaria Bucci,Andreas Papapetropoulos,Andreas Papapetropoulos,Valentina Vellecco,Zongmin Zhou,Altaany Zaid,Panagiotis Giannogonas,Anna Cantalupo,Sandeep Dhayade,Katia Karalis,Rui Wang,Robert Feil,Giuseppe Cirino +12 more
TLDR
The role of cGMP in the vascular responses to NaHS is confirmed and genetic deletion of PKG-I attenuates NaHS and L-cysteine-stimulated vasodilation and suggests that there is a cross-talk between KATP and PKG.Abstract:
A growing body of evidence suggests that hydrogen sulfide (H2S) is a signaling molecule in mammalian cells. In the cardiovascular system, H2S enhances vasodilation and angiogenesis. H2S-induced vasodilation is hypothesized to occur through ATP-sensitive potassium channels (KATP); however, we recently demonstrated that it also increases cGMP levels in tissues. Herein, we studied the involvement of cGMP-dependent protein kinase-I in H2S-induced vasorelaxation. The effect of H2S on vessel tone was studied in phenylephrine-contracted aortic rings with or without endothelium. cGMP levels were determined in cultured cells or isolated vessel by enzyme immunoassay. Pretreatment of aortic rings with sildenafil attenuated NaHS-induced relaxation, confirming previous findings that H2S is a phosphodiesterase inhibitor. In addition, vascular tissue levels of cGMP in cystathionine gamma lyase knockouts were lower than those in wild-type control mice. Treatment of aortic rings with NaHS, a fast releasing H2S donor, enhanced phosphorylation of vasodilator-stimulated phosphoprotein in a time-dependent manner, suggesting that cGMP-dependent protein kinase (PKG) is activated after exposure to H2S. Incubation of aortic rings with a PKG-I inhibitor (DT-2) attenuated NaHS-stimulated relaxation. Interestingly, vasodilatory responses to a slowly releasing H2S donor (GYY 4137) were unaffected by DT-2, suggesting that this donor dilates mouse aorta through PKG-independent pathways. Dilatory responses to NaHS and L-cysteine (a substrate for H2S production) were reduced in vessels of PKG-I knockout mice (PKG-I−/−). Moreover, glibenclamide inhibited NaHS-induced vasorelaxation in vessels from wild-type animals, but not PKG-I−/−, suggesting that there is a cross-talk between KATP and PKG. Our results confirm the role of cGMP in the vascular responses to NaHS and demonstrate that genetic deletion of PKG-I attenuates NaHS and L-cysteine-stimulated vasodilation.read more
Citations
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Journal ArticleDOI
Chemical Biology of H2S Signaling through Persulfidation.
TL;DR: The biologically relevant chemistry of H2S and the enzymatic routes for its production and oxidation are discussed and the roles ascribed to protein persulfidation in cell signaling pathways are discussed.
Journal ArticleDOI
Biogenesis of reactive sulfur species for signaling by hydrogen sulfide oxidation pathways
TL;DR: It is posited that sulfide oxidation pathways mediate sulfide signaling and that sulfurtransferases ensure target specificity and that sulfides, polysulfides and thiosulfate generate a series of reactive sulfur species that could modify target proteins.
Journal ArticleDOI
Hydrogen sulfide cytoprotective signaling is endothelial nitric oxide synthase-nitric oxide dependent
Adrienne L. King,David J. Polhemus,Shashi Bhushan,Hiroyuki Otsuka,Kazuhisa Kondo,Chad K. Nicholson,Jessica M. Bradley,Kazi N. Islam,John W. Calvert,Ya-Xiong Tao,Tammy R. Dugas,Eric E. Kelley,John W. Elrod,Paul L. Huang,Rui Wang,David J. Lefer +15 more
TL;DR: The results suggest that H2S-mediated cytoprotective signaling in the setting of I/R injury is dependent in large part on eNOS activation and NO generation, and indicates that hydrogen sulfide protects against multiple cardiovascular disease states in a similar manner as nitric oxide.
Journal ArticleDOI
International Union of Basic and Clinical Pharmacology. CII: Pharmacological Modulation of H2S Levels: H2S Donors and H2S Biosynthesis Inhibitors.
TL;DR: The present article overviews the currently known H 2S donors and H2S biosynthesis inhibitors, delineates their mode of action, and offers examples for their biologic effects and potential therapeutic utility.
Journal ArticleDOI
Key bioactive reaction products of the NO/H2S interaction are S/N-hybrid species, polysulfides, and nitroxyl
Miriam M. Cortese-Krott,Gunter G. C. Kuhnle,Alex Dyson,Bernadette O. Fernandez,Marian Grman,Jenna F. DuMond,Mark P. Barrow,George McLeod,Hidehiko Nakagawa,Karol Ondrias,Péter Nagy,S. Bruce King,Joseph E. Saavedra,Larry K. Keefer,Mervyn Singer,Malte Kelm,Anthony R. Butler,Martin Feelisch +17 more
TL;DR: The results unveil an unexpectedly rich network of coupled chemical reactions between NO and H2S/sulfide, suggesting that the bioactivity of either transmitter is governed by concomitant formation of polysulfides and anionic S/N-hybrid species.
References
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Journal ArticleDOI
H2S as a Physiologic Vasorelaxant: Hypertension in Mice with Deletion of Cystathionine γ-Lyase
Guangdong Yang,Guangdong Yang,Lingyun Wu,Bo Jiang,Wei Yang,Jiansong Qi,Kun Cao,Qinghe Meng,Asif K. Mustafa,Weitong Mu,Shengming Zhang,Solomon H. Snyder,Rui Wang,Rui Wang +13 more
TL;DR: It is shown that H2S is physiologically generated by cystathionine γ-lyase (CSE) and that genetic deletion of this enzyme in mice markedly reduces H 2S levels in the serum, heart, aorta, and other tissues.
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TL;DR: It is hypothesized that H2S is the third endogenous signaling gasotransmitter, besides nitric oxide and carbon monoxide, and this positioning will open an exciting field‐H2S physiology‐encompassing realization of the interaction of H1N1 and other gasOTransmitters, sulfurating modification of proteins, and the functional role of H2Sin multiple systems.
Journal ArticleDOI
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