Hydrogen Sulfide Is an Endogenous Inhibitor of Phosphodiesterase Activity

Abstract

Objective-Recent studies have demonstrated that hydrogen sulfide (H 2 S) is produced within the vessel wall from L-cysteine regulating several aspects of vascular homeostasis. H 2 S generated from cystathione ␥-lyase (CSE) contributes to vascular tone; however, the molecular mechanisms underlying the vasorelaxing effects of H 2 S are still under investigation. Methods and Results-Using isolated aortic rings, we observed that addition of L-cysteine led to a concentrationdependent relaxation that was prevented by the CSE inhibitors DL-propargylglyicine (PAG) and ␤-cyano-L-alanine (BCA). Moreover, incubation with PAG or BCA resulted in a rightward shift in sodium nitroprusside-and isoproterenol-induced relaxation. Aortic tissues exposed to PAG or BCA contained lower levels of cGMP, exposure of cells to exogenous H 2 S or overexpression of CSE raised cGMP concentration. RNA silencing of CSE expression reduced intracellular cGMP levels confirming a positive role for endogenous H 2 S on cGMP accumulation. The ability of H 2 S to enhance cGMP levels was greatly reduced by the nonselective phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine. Finally, addition of H 2 S to a cell-free system inhibited both cGMP and cAMP breakdown. Conclusion-These findings provide direct evidence that H 2 S acts as an endogenous inhibitor of phosphodiesterase activity and reinforce the notion that this gasotransmitter could be therapeutically exploited. Key Words: endothelium Ⅲ hypertension Ⅲ signal transduction Ⅲ vascular muscle Ⅲ vasodilation Ⅲ cystathione ␥-lyase Ⅲ hydrogen sulfide Ⅲ cAMP Ⅲ cGMP Ⅲ phosphodiesterase N itric oxide (NO) is believed to account for most of the endothelium-derived relaxing factor activity released within the vessel wall, at least in some vessels. 1 On muscarinic stimulation, NO is produced following the conversion of L-arginine to NO by endothelial nitric oxide synthase (eNOS). 2 NO diffuses from the endothelium to the underlying smooth muscle cell layer, where it stimulates soluble guanylate cyclase to produce cGMP. cGMP in turn activates protein kinase G (PKG), which initiates a cascade of events leading to relaxation. 2,3 Hydrogen sulfide (H 2 S) is emerging as a new gaseous signaling molecule in the cardiovascular system. 4,5 Vascular endothelial cells express cystathionine ␥-lyase (CSE) and produce measurable amounts of this gasotransmitter. 6 Recent evidence suggests that H 2 S exhibits endothelium-derived relaxing factor activity. 6 In addition, it has been shown that muscarinic stimulation leads to CSE activation in the endothelium, triggering the conversion of L-cysteine to H 2 S and that CSE, like eNOS, is a calcium/calmodulindependent enzyme. Therefore, within the vascular wall, these 2 pathways coexist and serve a similar function. The relative amounts of NO versus H 2 S likely depend on the vascular bed studied 7 or on the state of the tissue, eg, healthy versus diseased. 5,8 Mice with targeted disruption of the CSE locus (CSE null mice) exhibit hypertension, similarly to what is observe...

Hydrogen Sulfide Is an Endogenous Potentiator of T Cell Activation

“…We also investigated several previously defined targets of H 2 S in other systems, including K ϩ ATP channels, cGMP-dependent phosphodiesterases (51), and Akt (52) and found that these are not responsible for the effects of H 2 S on T cell activation (supplemental Fig. 1).…”

Hydrogen sulphide pathway contributes to the enhanced human platelet aggregation in hyperhomocysteinemia

“…CBS and CSE are differentially expressed in cardiovascular as well as in several other body districts (13). The physiological functions of H 2 S are mediated by a variety of molecular targets, including ion channels and signaling proteins (16)(17)(18). Alterations in H 2 S metabolism contribute to an array of cardiovascular disorders such as hypertension, atherosclerosis, heart failure, and diabetes (19).…”

Hydrogen Sulfide and Endothelial Dysfunction: Relationship with Nitric Oxide

“…H 2 S has been shown to dilate other isolated mammalian blood conduits in vitro, such as human internal mammary artery [103], mouse aorta and ear microcirculation [104,105], and newborn pig cerebral arterioles [106]. Consistent with these data, the systemic injection of NaHS at 10-50 activity in VSMCs, which leads to vasorelaxation in a PKG-dependent manner [48,111,112]. In primariy aortic ECs isolated from WT mice, H 2 S activates the PI-3K/Akt signaling pathway following increased eNOS phosphorylation in Ser-1177, thereby increasing NO production [47].…”