Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy.
Italian Liver Foundation, AREA SCIENCE PARK, 34149 Trieste, Italy.
Int J Mol Sci. 2021 Feb 19;22(4):2051. doi: 10.3390/ijms22042051.
Homocysteine (Hcy) is a sulfur-containing amino acid generated during methionine metabolism, accumulation of which may be caused by genetic defects or the deficit of vitamin B12 and folate. A serum level greater than 15 micro-mols/L is defined as hyperhomocysteinemia (HHcy). Hcy has many roles, the most important being the active participation in the transmethylation reactions, fundamental for the brain. Many studies focused on the role of homocysteine accumulation in vascular or degenerative neurological diseases, but the results are still undefined. More is known in cardiovascular disease. HHcy is a determinant for the development and progression of inflammation, atherosclerotic plaque formation, endothelium, arteriolar damage, smooth muscle cell proliferation, and altered-oxidative stress response. Conversely, few studies focused on the relationship between HHcy and small vessel disease (SVD), despite the evidence that mice with HHcy showed a significant end-feet disruption of astrocytes with a diffuse SVD. A severe reduction of vascular aquaporin-4-water channels, lower levels of high-functioning potassium channels, and higher metalloproteinases are also observed. HHcy modulates the N-homocysteinylation process, promoting a pro-coagulative state and damage of the cellular protein integrity. This altered process could be directly involved in the altered endothelium activation, typical of SVD and protein quality, inhibiting the ubiquitin-proteasome system control. HHcy also promotes a constant enhancement of microglia activation, inducing the sustained pro-inflammatory status observed in SVD. This review article addresses the possible role of HHcy in small-vessel disease and understands its pathogenic impact.
同型半胱氨酸（Hcy）是蛋氨酸代谢过程中产生的含硫氨基酸，其积累可能是由于遗传缺陷或维生素 B12 和叶酸的缺乏。血清水平大于 15 微摩尔/升被定义为高同型半胱氨酸血症（HHcy）。Hcy 有许多作用，最重要的是积极参与转甲基反应，这对大脑至关重要。许多研究集中在同型半胱氨酸积累在血管或退行性神经疾病中的作用，但结果仍不确定。在心血管疾病中了解得更多。HHcy 是炎症、动脉粥样硬化斑块形成、内皮细胞、小动脉损伤、平滑肌细胞增殖和氧化应激反应改变的发展和进展的决定因素。相反，尽管有证据表明 HHcy 小鼠的星形胶质细胞终足明显中断，弥漫性 SVD，但很少有研究关注 HHcy 与小血管疾病（SVD）之间的关系。血管水通道蛋白-4 水通道严重减少，高水平的高效钾通道和更高的金属蛋白酶也观察到。HHcy 调节 N-同型半胱氨酸化过程，促进促凝状态和细胞蛋白完整性的损伤。这一改变的过程可能直接参与了 SVD 中改变的内皮细胞激活和蛋白质质量的改变，抑制了泛素-蛋白酶体系统的控制。HHcy 还促进小胶质细胞持续激活，诱导 SVD 中观察到的持续促炎状态。这篇综述文章探讨了 HHcy 在小血管疾病中的可能作用，并了解其发病机制的影响。
