Physiological and pharmacological features of the novel gasotransmitter: hydrogen sulfide

Abstract

Hydrogen sulfide (H(2)S) has been known for hundreds of years because of its poisoning effect. Once the basal bio-production became evident its pathophysiological role started to be investigated in depth. H(2)S is a gas that can be formed by the action of two enzymes, cystathionine gamma-lyase and cystathionine beta-synthase, both involved in the metabolism of cysteine. It has several features in common with the other two well known "gasotransmitters" (nitric oxide and carbon monoxide) in the biological systems. These three gasses share some biological targets; however, they also have dissimilarities. For instance, the three gases target heme-proteins and open K(ATP) channels; H(2)S as NO is an antioxidant, but in contrast to the latter molecule, H(2)S does not directly form radicals. In the last years H(2)S has been implicated in several physiological and pathophysiological processes such as long term synaptic potentiation, vasorelaxation, pro- and anti-inflammatory conditions, cardiac inotropism regulation, cardioprotection, and several other physiological mechanisms. We will focus on the biological role of H(2)S as a molecule able to trigger cell signaling. Our attention will be particularly devoted on the effects in cardiovascular system and in cardioprotection. We will also provide available information on H(2)S-donating drugs which have so far been tested in order to conjugate the beneficial effect of H(2)S with other pharmaceutical properties.

Fig. 1

Enzymatic pathways of H₂S production in mammalian cells. On the left panel the cytosolic pathway leading to the formation of H₂S from methionine. On the right panel formation of H₂S in mitochondria from cysteine. MAT: methionine adenosyltransferase. GNMT: glycine N-methyltransferase. CBS: cystathionine β-synthase. CSE: cysthationine γ-lyase. AAT: aspartate aminotransferase. MPST: 3-mercaptopyruvate sulfur transferase. Mancardi et al.

Fig. 2

Proposed signaling pathways of H₂S in cardioprotection: representation of the putative cascade of reactions triggered by molecular H₂S. The yellow solid line indicates the direct inhibitory pathway to the β-adrenergic receptors and the dashed yellow line indicates the indirect inhibitory action on L-type Ca²⁺ channels. Red lines: direct activation of membrane and mitochondrial K_ATP channels with consequent activation/translocation of PKC. Black lines represent mechanism of early and late cardioprotection (SWOP). NCX: Na⁺/Ca²⁺ exchanger. SERCA: Sarco/Endoplasmatic Reticulum Ca²⁺-ATPase. RyR: Ryanodine Receptor. PKC: Protein Kinase C. PKA: Protein Kinase A. AC: Adelynate Cyclase. ROS: Reactive Oxygen Species. ETC: electron transport chain. mPTP: mitochondrial Permeability Transition Pore. SWOP: second window of protection. Mancardi et al.