ABSTRACT
Title
Hydrogen Sulphide Is An Endogenous Inhibitor Of Phosphodiesterase Activity
Authors
M. Bucci1, A. Papapetropoulos2, V. Vellecco1, A. Pyriochou2, F. Roviezzo1, V. Brancaleone1, G. Cirino1
1Department of Experimental Pharmacology, Faculty of Pharmacy, University of Naples –Federico II- Naples, Italy; 2Laboratory for Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, Greece
1Department of Experimental Pharmacology, Faculty of Pharmacy, University of Naples –Federico II- Naples, Italy; 2Laboratory for Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, Greece
Abstract
Recent studies have demonstrated that hydrogen sulphide (H2S) is produced within the vessel wall from L-cysteine regulating several aspects of vascular homeostasis. H2S generated from cystathione gamma lyase (CSE) contributes to vascular tone; however, the molecular mechanisms underlying the vasorelaxing effects of H2S are still under investigation (1-4).
Using isolated aortic rings, we observed that addition of L-cysteine led to a concentration-dependent relaxation that was prevented by the CSE inhibitors DL-propargylglyicine (PGG) and β-cyano-L-alanine (BCA). Moreover, incubation with PGG or BCA resulted in a rightward shift in sodium nitroprusside-induced relaxation. While aortic tissues exposed to PGG or BCA contained lower levels of cGMP, exposure of cells to exogenous H2S or overexpression of CSE raised cGMP concentration. RNA silencing of CSE expression reduced intracellular cGMP levels confirming a positive role for endogenous H2S on cGMP accumulation. The ability of H2S to enhance cGMP levels was greatly reduced by the non-selective phoshodiesterase (PDE) inhibitor isobutyl-methylxanthine. Finally, addition of H2S to a cell free system inhibited cyclic nucleotide breakdown. These findings provide direct evidence that H2S act as an endogenous inhibitor of PDE activity and reinforce the notion that this gasotrasmitter could be therapeutically exploited.
1)Yang G et al., H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase. . 2008 Science;322:587-590.
2)Brancaleone V et al., Biosynthesis of H2S is impaired in non-obese diabetic (NOD) mice. 2008 Br J Pharmacol.;155:673-680.
3)Li L et al., Actions and interactions of nitric oxide, carbon monoxide and hydrogen sulphide in the cardiovascular system and in inflammation- a tale of three gases! 2009 Pharmacol Ther;123:386-400.
4)Sanderson K. Hydrogen sulphide biology: emissions control. 2009 Nature.;459:500-502.
Using isolated aortic rings, we observed that addition of L-cysteine led to a concentration-dependent relaxation that was prevented by the CSE inhibitors DL-propargylglyicine (PGG) and β-cyano-L-alanine (BCA). Moreover, incubation with PGG or BCA resulted in a rightward shift in sodium nitroprusside-induced relaxation. While aortic tissues exposed to PGG or BCA contained lower levels of cGMP, exposure of cells to exogenous H2S or overexpression of CSE raised cGMP concentration. RNA silencing of CSE expression reduced intracellular cGMP levels confirming a positive role for endogenous H2S on cGMP accumulation. The ability of H2S to enhance cGMP levels was greatly reduced by the non-selective phoshodiesterase (PDE) inhibitor isobutyl-methylxanthine. Finally, addition of H2S to a cell free system inhibited cyclic nucleotide breakdown. These findings provide direct evidence that H2S act as an endogenous inhibitor of PDE activity and reinforce the notion that this gasotrasmitter could be therapeutically exploited.
1)Yang G et al., H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase. . 2008 Science;322:587-590.
2)Brancaleone V et al., Biosynthesis of H2S is impaired in non-obese diabetic (NOD) mice. 2008 Br J Pharmacol.;155:673-680.
3)Li L et al., Actions and interactions of nitric oxide, carbon monoxide and hydrogen sulphide in the cardiovascular system and in inflammation- a tale of three gases! 2009 Pharmacol Ther;123:386-400.
4)Sanderson K. Hydrogen sulphide biology: emissions control. 2009 Nature.;459:500-502.