Severe Hyperhomocysteinemia Promotes Bone Marrow–Derived and Resident Inflammatory Monocyte Differentiation and Atherosclerosis in LDLr/CBS-Deficient Mice

Abstract

Background This study examined the causative role of hyperhomocysteinemia (HHcy) in atherogenesis and its effect on inflammatory monocyte (MC) differentiation. Methods and Results We generated a novel HHcy and hyperlipidemia mouse model, in which cystathionine β-synthase (CBS) and low-density lipoprotein receptor (LDLr) genes were deficient (Ldlr−/− Cbs−/+). Severe HHcy (plasma homocysteine (Hcy)=275 µM) was induced by a high methionine diet containing sufficient basal levels of B vitamins. Plasma Hcy levels were lowered to 46 µM from 244 µM by vitamin supplementation, which elevated plasma folate levels. Bone marrow (BM)-derived cells were traced by the transplantation of BM cells from enhanced green fluorescent protein (EGFP) transgenic mice after sub-lethal irradiation of the recipient. HHcy accelerated atherosclerosis and promoted Ly6Chigh inflammatory MC differentiation of both BM- and tissue-origins in the aortas and peripheral tissues. It also elevated plasma levels of TNF-α, IL-6 and MCP-1; increased vessel wall MC accumulation; and macrophage maturation. Hcy-lowering therapy reversed HHcy-induced lesion formation, plasma cytokine increase, and blood and vessel inflammatory MC (Ly6Chigh+middle) accumulation. Plasma Hcy levels were positively correlated with plasma levels of pro-inflammatory cytokines. In primary mouse splenocytes, L-Hcy promoted rIFNγ-induced inflammatory MC differentiation, as well as increased TNF-α, IL-6, and superoxide anion production in inflammatory MC subsets. Antioxidants and folic acid reversed L-Hcy-induced inflammatory MC differentiation and oxidative stress in inflammatory MC subsets. Conclusion HHcy causes vessel wall inflammatory MC differentiation and macrophage maturation of both BM- and tissue-origins leading to atherosclerosis via an oxidative stress related mechanism.

Hyperhomocysteinemia and Methylenetetrahydrofolate Reductase Polymorphism in Cervical Artery Dissection: A Meta-Analysis

“…HHcy is an independent risk factor for coronary artery disease, Alzheimer's disease and stroke [12,13,14,15]. Mechanistically, HHcy promotes oxidative stress [16], accelerates vascular smooth muscle cell migration, adventitial collagen accumulation and neointima formation [17,18]. Methylenetetrahydrofolate reductase (MTHFR) is a rate-limiting enzyme in the methionine metabolism pathway that catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cosubstrate for homocysteine remethylation to methionine [19].…”

Intermedin Restores Hyperhomocysteinemia-induced Macrophage Polarization and Improves Insulin Resistance in Mice

“…Insulin resistance is promoted by a transition in macrophage polarization from an anti-inflammatory M2 activation state to an inflammatory M1 activation state (14,(35)(36)(37). Previous reports have indicated that HHcy promotes the differentiation of Ly6C-high inflammatory monocytes in an atherosclerosis mouse model (19). Another recent study demonstrated that Hcy induces M1 polarization and converts M2 to an M1 subtype in vitro (26).…”

“…Insulin resistance was promoted by a transition in macrophage polarization from an alternative M2 state to a pro-inflammatory M1 state (13,14,24,25). It has been reported that HHcy promotes inflammatory monocyte differentiation (19). Combined with LPS, Hcy induced the M1 polarization of a macrophage cell line, RAW264.7, in vitro (26).…”

Effect of MTHFR A1298C and MTRR A66G genetic mutations on homocysteine levels in the Chinese population: a systematic review and meta-analysis

“…[3] Possible mechanisms by which Hcy contributes to vascular damage include inhibiting endothelial cell (EC) growth and post-injury endothelial repair, [4,5] inducing endothelial dysfunction, [6] promoting vascular remodeling, [7] and inflammatory monocyte differentiation. [8,9] Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) are the two key enzymes responsible for the remethylation of Hcy to methionine in the one-carbon metabolic pathway. [10] MTHFR converts 5,10-methylene-tetrahydrofolate (THF) into 5-methyl-THF, the dominant circulating form of folate.…”