Tyagi Neetu, Moshal Karni S, Ovechkin Alexander V, Rodriguez Walter, Steed Mesia, Henderson Brooke, Roberts Andrew M, Joshua Irving G, Tyagi Suresh C
Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA.
J Cell Biochem. 2005 Nov 1;96(4):665-71. doi: 10.1002/jcb.20578.
Formation of homocysteine (Hcy) is the constitutive process of gene methylation. Hcy is primarily synthesized by de-methylation of methionine, in which s-adenosyl-methionine (SAM) is converted to s-adenosyl-homocysteine (SAH) by methyltransferase (MT). SAH is then hydrolyzed to Hcy and adenosine by SAH-hydrolase (SAHH). The accumulation of Hcy leads to increased cellular oxidative stress in which mitochondrial thioredoxin, and peroxiredoxin are decreased and NADH oxidase activity is increased. In this process, Ca2+-dependent mitochondrial nitric oxide synthase (mtNOS) and calpain are induced which lead to cytoskeletal de-arrangement and cellular remodeling. This process generates peroxinitrite and nitrotyrosine in contractile proteins which causes vascular dysfunction. Chronic exposure to Hcy instigates endothelial and vascular dysfunction and increases vascular resistance causing systemic hypertension. To compensate, the heart increases its load which creates adverse cardiac remodeling in which the elastin/collagen ratio is reduced, causing cardiac stiffness and diastolic heart failure in hyperhomocysteinemia.
同型半胱氨酸（Hcy）的形成是基因甲基化的组成过程。Hcy主要通过蛋氨酸的去甲基化合成，其中S-腺苷甲硫氨酸（SAM）被甲基转移酶（MT）转化为S-腺苷同型半胱氨酸（SAH）。然后SAH被SAH水解酶（SAHH）水解为Hcy和腺苷。Hcy的积累导致细胞氧化应激增加，其中线粒体硫氧还蛋白和过氧化物酶减少，NADH氧化酶活性增加。在此过程中，诱导了Ca2+依赖性线粒体一氧化氮合酶（mtNOS）和钙蛋白酶，导致细胞骨架紊乱和细胞重塑。这个过程在收缩蛋白中产生过氧亚硝酸盐和硝基酪氨酸，导致血管功能障碍。长期暴露于Hcy会引发内皮和血管功能障碍，增加血管阻力，导致系统性高血压。为了代偿，心脏增加其负荷，这会导致不良的心脏重塑，其中弹性蛋白/胶原蛋白比例降低，导致高同型半胱氨酸血症中的心脏僵硬和舒张性心力衰竭。
