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.
Highlights
Hydrogen sulfide is a small gaseous compound that together with nitric oxide and carbon monoxide comprises the gasotransmitter family [1,2]
The observed rightward shift of the NaHS dose-response in the presence of sildenafil (2.861024 M vs. 8.561025 M vehicle vs sildenafil p,0.001) is consistent with the notion that NaHSstimulated vasodilation is at least in part mediated by PDE5 inhibition
Based on the ability of H2S to increase cGMP levels in vascular tissues, we investigated the role of this cyclic nucleotide in H2S-induced vasorelaxation and the interaction between cGMP-regulated pathways and KATP channels in mediating the effects of H2S
Summary
Hydrogen sulfide is a small gaseous compound that together with nitric oxide and carbon monoxide comprises the gasotransmitter family [1,2]. Viewed as environmental pollutants and biohazardous compounds gasotransmitters are widely accepted for their important roles in physiology and disease [3,4,5,6]. Hydrogen sulfide is the newest and least studied gasotransmitter. Recently there has been a surge of interest in hydrogen sulfide biology leading to important observations regarding its role in mammalian cells. The enzymes implicated in H2S generation include cystathionine beta synthase (CBS), cystathionine gamma lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3MST) [5,9]. While 3MST has been shown to be present in endothelial cells [10], this enzyme is relatively less studied and its role in cardiovascular biology is unclear
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