Nitric oxide and hydrogen sulfide: the gasotransmitter paradigm of the vascular system

Abstract

There are several reviews on NO and hydrogen sulfide (H₂ S) and their role in vascular diseases in the current relevant literature. The aim of this review is to discuss, within the limits of present knowledge, the interconnection between these two gasotransmitters in vascular function. In particular, the review focuses on the role played by the balance between the NO and H₂ S pathways in either physiological or pathological conditions. The distinction between physiology and pathology has been made in order to dissect the molecular basis of this crosstalk, highlighting how and if this balance varies, depending upon the vascular status. Perspectives and possible novel therapeutic approaches are also discussed.

Linked articles: This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc.

Figure 1

Representative simplified scheme summarizing the main findings discussed. The diagram outlines the interaction between NO and H₂S in physiological (HEALTHY) and pathological (IBVD) conditions. HEALTHY: In endothelium, eNOS is bound to CAV‐1, a resident protein of caveolae that keeps eNOS in a less active state. When intracellular Ca²⁺ rises, Ca²⁺‐calmodulin complex is formed and binds eNOS. This event contributes to the displacement of eNOS from the negative control of CAV‐1, leading to enzyme activation and NO production. At the same time, Ca²⁺‐calmodulin complex also activates CSE, leading to H₂S biosynthesis. Being gases, NO and H₂S diffuse into smooth muscle cells reaching their own targets: sGC for NO and PDE for H₂S. NO activates sGC leading to cGMP increase, while H₂S inhibits PDE reducing cGMP degradation. cGMP, by interacting with PKG, activates the downstream signalling that leads to vasodilatation. In addition, H₂S acts as an opener of K_ATP channels, expressed on smooth muscle cells leading to efflux of K⁺ ions from the cells. This event reduces calcium influx into the cells contributing to vessel relaxation. CSE is also expressed in smooth muscle cells where it actively produces H₂S. IBVD: vascular diseases are characterized by an overproduction of ROS that induce oxidative stress. This condition damages the endothelium, impairing both eNOS and CSE activity with consequent reduction of both NO and H₂S biosynthesis. The oxidative stress can also affect K_ATP channel activity. The limited amount of NO provided by a damaged endothelium, still can activate the signal transduction pathway relying on the contribution of smooth muscle cell‐generated H₂S that in turn, by inhibiting PDE, allows a production of cGMP within the threshold necessary to trigger the downstream signal. Solid line: activation; dotted line: inhibition.