ISSN: 2643-3966 Lopes. Int Arch Cardiovasc Dis 2018, 2:008 Volume 2 | Issue 1 Open Access International Archives of Cardiovascular Diseases REVIEW ARTICLE Hyperhomocysteinemia: How Does it Affect the Development of Cardiovascular Disease? * Lopes Cardoso I Check for updates Health Sciences Faculty, Fernando Pessoa University, Portugal *Corresponding author: Inês Lopes Cardoso, Health Sciences Faculty, Fernando Pessoa University, Rua Carlos da Maia, 296, 4200-150 Porto, Portugal, Tel: 351-225071300 of the ones having atherosclerotic vascular disease, 13- Abstract 47% show moderate to intermediate hyperhomocyste- Homocysteine is an amino acid with an SH group, metab- ine levels [1,2]. olised by the remethylation and transsulfuration pathways. Several genetic and environmental factors (like deficient Changes in plasma homocysteine levels can result nutrition status, systemic disease or consumption of certain from the presence of several factors including physio- drugs), can lead to changes in the levels of plasma homo- cysteine. logical, genetic, nutritional, drug induced and hormonal factors. First studies indicating mild hyperhomocyste- Nowadays, hyperhomocysteinemia is considered an impor- tant and independent risk factor for atherosclerosis and car- inemia as an independent risk factor for cardiovascular diovascular disease. disease, with a prevalence of approximately 5% in the general population, date from the 80th decade [3-6]. Several pathological mechanisms have been proposed for the effect of hyperhomocysteinemia in the development of Metabolism of Homocysteine cardiovascular disease. Among them are DNA methylation, decreased protein S-nitrosylation, production of reactive ox- Homocysteine is an amino acid with SH group, pro- idative species and decrease in nitric oxide formation. duced exclusively from methionine which, as an essen- Main strategies being tested for the treatment of this condi- tial amino acid, comes from food diet [7]. Homocysteine tion involve supplementation of folic acid, vitamins B6, B12 metabolism involves two different metabolic pathways: or riboflavin. From these, increased plasma folic acid lev- the remethylation and the transsulfuration pathways els by folate-rich diet or pharmacological supplementation seems to be the most effective. (Figure 1) [8,9]. Keywords The remethylation pathway, mainly occurring in Homocysteine, Cardiovascular disease, Folic acid, Vitamin starvation conditions, involves the catabolism of -me B6, Vitamin B12, Riboflavin thionine. In the first step, methionine reacts with ATP leading to the formation of S-adenosylmethionine. This molecule then loses the methyl group attached with Introduction the sulphur atom (present in methionine), forming S-adenosyl-homocysteine. The methyl group released Cardiovascular diseases are the main cause of death by S-adenosylmethionine can be transferred by meth- in developed countries. Several risk factors are involved yl-transferases to several substrates (methyl acceptors) in its development like family background, hypercholes- like proteins, DNA or phospholipids (Figure 1). terolemia, obesity, diabetes mellitus and environmental factors such as sedentarism. High level of plasma ho- The next step is the hydrolysis of S-adenosyl-homo- mocysteine also represents a risk factor, independent cysteine to produce homocysteine. Later, the sulphur of other factors. It is observed that 5-7% of general atom of homocysteine can be transferred to serine en- population show hyperhomocysteinemia, and of those, tering the transsulfuration pathway described below. Citation: Lopes CI (2018) Hyperhomocysteinemia: How Does it Affect the Development of Cardiovas- cular Disease?. Int Arch Cardiovasc Dis 2:008 Accepted: August 25, 2018; Published: August 27, 2018 Copyright: © 2018 Lopes CI. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Lopes. Int Arch Cardiovasc Dis 2018, 2:008 • Page 1 of 12 • ISSN: 2643-3966 Methionine cycle Folate cycle Food diet Serine Remeth ylation pathway Methionin Tetrahydro folate Glycine S-adenosylmethionine Methionine 5,10-methylene Methylated acceptor Vitamin B12 synthetase tetrahydrofolate Methyl a cceptor S-adenosyl-homocysteine MTHFR + NADP Homocysteine 5-Methyl Riboflavin tetrahydrofolate Vitamin B6 Cystathionine-β-synthase NADPH Cystathionine Tran ssulfuration pathway Cysteine Sulphate Urine Figure 1: Homocysteine metabolism (adapted from [10]). Homocysteine can also be used to regenerate methi- sequentially involved: Cystathionine β-synthase (CBS) onine, by the vitamin B12 dependent enzyme methi- and cystathionine lyase. The active form of vitamin B6 - onine synthetase (MS) that transfers a methyl group pyridoxal phosphate - is a cofactor of CBS that converts given by 5-methyltetrahydrofolate to homocysteine. homocysteine into cystathionine, first step of the trans- In most cells, this is the main or unique pathway of sulfuration pathway (Figure 1). The α-ketobutirate can conversion of homocysteine to methionine. This ami- be converted into propionyl-CoA that is further trans- no acid will enter a new cycle of donation of methyl formed into succinyl-CoA (an intermediate of the Krebs group. Another product of this reaction is tetrahydro- cycle). It is evident the importance of B vitamins in ho- folate, that will be reconverted to 5-methyltetrahydro- mocysteine metabolism, since these molecules play a folate through the folate cycle, where the conversion crucial role as enzyme cofactors. Vitamin B6 is required of 5,10-methylenetetrahydrofolate to 5-methyltetrahy- for CBS activity while vitamin B12 is the cofactor of MS. drofolate is catalysed by the FAD dependent enzyme, Another important vitamin for homocysteine metabo- methylenetetrahydrofolate reductase (MTHFR) [10]. lism is riboflavin that is necessary for MTHFR function. MTHFR enzyme has an important function since it reg- Homocysteine can be found in plasma in the free ulates the availability of 5-methyltetrahydrofolate for form (around 20-30%), but most of it (70-80%) is associ- homocysteine remethylation. The reaction catalysed by ated with plasma proteins, mainly albumin. MS allows the connection between the methionine and the folate cycles (Figure 1). Plasma homocysteine present in the free form can also be in the oxidized form, giving rise to two types The transsulfuration pathway, that takes place in of disulphides: Homocysteine dimers (homocystine) or cases of methionine overload, involves the catabo- homocysteine-cysteine dimers. From the free homocys- lism of homocysteine to sulphate, later excreted in the teine fraction, 2 to 5% correspond to its reduced form. urine. The sulphur atom present in homocysteine is Total plasma homocysteine is the sum of all free forms transferred to serine leading to the production of cyste- and forms attached to proteins [11]. ine, while the nitrogenated group and the carbons that belonged to homocysteine are released as ammonium Concerning plasma homocysteine levels, there is no and α-ketobutirate. In this process, two enzymes are consensus about the upper standard limits for healthy Lopes. Int Arch Cardiovasc Dis 2018, 2:008 • Page 2 of 12 • ISSN: 2643-3966 individuals, ranging from 5 to 15 µmol/L [2,12,13]. How- Li, et al. [25] detected eleven mutations and ever, some studies have shown that an upper limit of eight (IVS3+1G>A, p.T493fsX46, p.T236N, p.L230Q, p. 15 µmol/L is too high in well-nourished populations K72I, p.S201ProfsX36, p.M337IfsX115 and IVS14-1G>C) without vitamin deficiencies [14]. Moreover, plasma were novel. The remaining three mutations (p.R125Q, homocysteine concentrations vary with age and gender p.T257M and p.G116R) had been previously reported [12,13]. [25]. It has been documented the existence of substan- Moreover, Voskoboeva, et al. [26] detected one tial cardiovascular risk with plasma homocysteine lev- new nonsense mutation (Q368Term), one new mis- els between 10 and 15 µmol/L. However, on the other sense mutation (р.D444Y) and three novel small dele- hand, de Bree, et al. [15] observed that an increase of tions (c.1560-1569delCACCGGGAAG; c.216-217delAT; 5 µmol/L in plasma homocysteine concentration, rises c.1498-1499delT) in Russian patients. 1.03 the risk of coronary heart disease mortality. These Other rare genetic changes can cause an up to 20 results do not support the idea of an influence of hy- times increase in plasma homocysteine and lead to perhomocysteinemia in increased risk of cardiovascular the development of severe hyperhomocysteinemia disease [15]. and result from deficiency in the MTHFR enzyme of Genetic Factors Involved in the Development the remethylation pathway and 10 different mutations of Hyperhomocysteinemia in this gene have already been described (located at 1p36.3) [18,19]. The clinical syndrome homocystinuria, identified al- most 60 years ago [16,17], is a disorder with autosomal The major known genetic determinant of mild hyper- recessive transmission. Phenotypic characteristics in- homocysteinemia in the general population is a thermo- clude thromboembolism and vascular occlusion, chang- labile missense mutation, that leads to the change of al- es in long bones, ocular displacement, mental retarda- anine per valine, resulting from the substitution of cyto- tion and varying degrees of neurological impairment sine per thymine in base 677 of the gene. This mutation [10,18,19]. leads