Clinical Applications for Gasotransmitters in the Cardiovascular System: Are We There Yet?

Abstract

Ischemia is the underlying mechanism in a wide variety of acute and persistent pathologies. As such, understanding the fine intracellular events occurring during (and after) the restriction of blood supply is pivotal to improving the outcomes in clinical settings. Among others, gaseous signaling molecules constitutively produced by mammalian cells (gasotransmitters) have been shown to be of potential interest for clinical treatment of ischemia/reperfusion injury. Nitric oxide (NO and its sibling, HNO), hydrogen sulfide (H₂S), and carbon monoxide (CO) have long been proven to be cytoprotective in basic science experiments, and they are now awaiting confirmation with clinical trials. The aim of this work is to review the literature and the clinical trials database to address the state of development of potential therapeutic applications for NO, H₂S, and CO and the clinical scenarios where they are more promising.

Keywords: carbon monoxide; cardioprotection; clinical trials; hydrogen sulfide; ischemia; nitric oxide; reperfusion.

Figure 1

Biosynthesis of the three gasotransmitters. H₂S is synthesized by cystathionine β-synthase (CBS) or cystathionine γ-lyase (CSE) by converting L-cysteine to L-serine or pyruvate and NH₃. L-cysteine can also be metabolized in 3-Mercaptopyruvate via cysteine aminotransferase (CAT) and then converted into H₂S and pyruvate by mercaptopyruvate transferase (3MST); CO is synthesized by heme oxygenases (HO-1, HO-2, or HO-3) by oxidizing heme with the help of cofactors, such as NADPH and O₂, to produce CO, biliverdin, and ferritin; NO is synthesized by a family of NO synthases (nNOS, eNOS, or iNOS) that catalyzes the oxidation of L-arginine to L-citrulline producing NO in the process. O₂ and NADPH are necessary co-factors.

Figure 2

Main targets of the three gasotransmitters in a cardiovascular scenario. NO, H₂S, and CO target mitochondria with multiple effects. NO favors S-nitrosylation (SNO) on mitochondrial proteins and also increases the expression of soluble guanylate cyclase (sGC), activating the related pathways with the aim to inhibit cardiac hypertrophy. NO also induces vasorelaxation through protein kinase G (PKG) activation. CO increases ATP production by targeting mitochondria, and it is able to regulate the NO/sGC pathway, whereas H₂S has a scavenger function, which reduces ROS and inhibits apoptosis.

Figure 3

Cardiac effects of the three gasotransmitters. H₂S, by scavenging ROS, reduces vascular oxidative stress and so reduces inflammation, cardiac fibrosis, cardiomyocyte apoptosis, and endothelial dysfunction. NO has anti-inflammatory effects related to the inhibition of platelet aggregation and leukocyte adhesion. CO has anti-inflammatory and anti-proliferative activity. In addition, CO has a vasoactive, anti-apoptotic, anti-thrombotic, and antioxidant function.