Increase of Homocysteinemia/Hydrogen Sulfide (Hcy/H2S) Ratio Raises Cardiovascular Injuries

Review Article

J Cardiovasc Disord. 2021; 7(2): 1046.

Increase of Homocysteinemia/Hydrogen Sulfide (Hcy/H2S) Ratio Raises Cardiovascular Injuries

Cacciapuoti F*

Department of Internal Medicine, “Luigi Vanvitelli”-Campania-University, Italy

*Corresponding author: Federico Cacciapuoti, Department of Internal Medicine, “Luigi Vanvitelli” Campania University, Piazza L. Miraglia, 2 Naples, Italy

Received: July 02, 2021; Accepted:July 30, 2021; Published: August 06, 2021


Increased Homocysteine Levels (HHcy) is an independent risk factor for atherosclerosis. On the other hand, hydrogen sulfide (H2S) exerts a protection against cardiovascular injuries. On the contrary, accumulating evidences showed that downregulation of defective catabolism of HHcy, with reduced H2S synthesis, is involved in the pathogenesis of a variety of cardiovascular diseases. In that occurrence, the detrimental actions on cardiovascular structures performed by HHcy are added to the negative consequences of reduced H2S (in part unlike each HHcy) on cardiovascular system. Therefore, when the reduced re-methylation pathway of Hcy towards Met (resulting in HHcy) is contemporarily added to the decreased trans-sulfuration pathway (inducing a reduction of H2S synthesis) cardiovascular impairment significantly increases.

Keywords: Homocysteine; Hydrodgen sulfide; Re-methylation pathway; Trans-sulfuration pathway; Endothelial dysfunction; Cardiovascular injuries


Hcy: Homocysteine; Met: Methionine; MTHFR: Methylene- Tetra-Hydrofolate Reductase; MS: Methionine; Synthase; GHS”: Glutathione; MAT: Methionine-Adenosyl-Transferase; SAM: S-Adenosyl-Methionine; SAH: S-Adenosyl-Homocysteine; DNA: Desossi-Nucleic Acid; RNA: Ribo-Nucleic Acid; DMG: Di-Methyl- Glycine; CΒS: Cystationine-Β-Synthase; CSE: Cystationine-Gamma- Lyase; 3-MST: 3-Mercaptopyruvate-Sulfur-Transferase; H2S: Hydrogen Sulfide; HHcy: HyperHomocysteine; ED: Endothelial Dysfunction; Ecs: Endothelial Cells; NO: Nitric Oxide; DDAH: Dimethylarginine-Dimethyl-Amino Hydrolase; NOS: Nitric Oxide Synthase; ROS: Reactive Oxygen Species; ONOO: Peroxynitrite; TxA2: Tromboxane A2; ADP: Adenosyl-D-Phosphate; OH: Hydroxyl Radical; H2O2: Hydrogen Peroxide; cAMP: cyclic Adenosine-Mono- Phosphate; VSMC: Vascular Smooth Muscle Cell; ATP: Adenosin- Tri-Phosphate; VCAM: Adhesion Molecule; MCP-1: Monocyte Chemoattractant Protein-1; NF-kB: Nuclear Factor kB; CAM-1: Adhesion Molecule-1; NaHS: Sodium Hydrosulfide; I/R: Ischemia/ Reperfusion


Homocysteine (Hcy) is a sulfur-containing amino acid derived, as metabolite, by a dietary Methionine (Met). That is present in several aliments, such as meat, fish and dietary products. Further meta bolization of Hcy happens by two means: remethylation to Met and trans-sulfuration to Cysteine and Glutathione (GSH) [1,2]. The former involves the enzymes MethyleneTetra-Hydro-Folate Reductase (MTHFR) and Methionine Synthase (MS). In this pathway, Met is subsequently activated in S-Adenosyl-Methionine (SAM) by Methionine Adenosyl-Transferase (MAT). SAM acts as a methyl donor (-CH3) to some substrates, such as DNA, neurotransmitters, RNA, proteins, amino acids, phospholipids, monoamines, and others by a process of trans-methylation [3,4]. Subsequently, SAM is changed in S-Adenosyl-Homocysteine (SAH). A second route of Hcy re-methylation in not-dependent on folate and requires Betaine as 1C donor (Betaine cycle). The reaction results in the production of Dimethylglycine (DMG) and happens in the liver and kidney alone. Further Hcy-catabolization happens via transsulfuration pathway (Figure 1). In this route, Hcy is converted in Cystathionine by the enzyme Cystathionine-Β-Synthase (CBS). That is acted by the enzyme Cystathionine-gamma-Lyase (CSE) to generate Cysteine. In turn Cysteine, through the enzyme 3-Mercaptopyruvate Sulfur- Transferase (3-MST), produces a gaseous and malodorous mediator toxic gas called Hydrogen Sulfide (H2S). From the gas drives the powerful antioxidant GHS [5]. Among three enzymes involved in transsulfuration pathway, CBS and CSE participate in the interconversion of Hcy in Cysteine. The steps of transsulfuration pathway until the H2S synthesis are schematized in Figure 2. The majority of studies in this pathway was performed on animals and has focused for CSE [6]. It must be added that, when dietary Met intake is low prevails the remethylation pathway; on the contrary, when Met intake is high prevails the trans-sulfuration pathway.