Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model

Abstract

Methods Induction of HHcy.Male apoE-null mice (15-16) (backcrossed ten generations into C57BL/6J) were obtained from The Jackson Laboratories (Bar Harbor, Maine, USA). At age 4 weeks, mice were fed standard rodent chow 5001C (diet A), a diet enriched in methionine Although hyperhomocysteinemia (HHcy) is a well-known risk factor for the development of cardiovascular disease, the underlying molecular mechanisms are not fully elucidated. Here we show that induction of HHcy in apoE-null mice by a diet enriched in methionine but depleted in folate and vitamins B6 and B12 increased atherosclerotic lesion area and complexity, and enhanced expression of receptor for advanced glycation end products (RAGE), VCAM-1, tissue factor, and MMP-9 in the vasculature. These homocysteine-mediated (HC-mediated) effects were significantly suppressed, in parallel with decreased levels of plasma HC, upon dietary supplementation with folate and vitamins B6/B12. These findings implicate HHcy in atherosclerotic plaque progression and stability, and they suggest that dietary enrichment in vitamins essential for the metabolism of HC may impart protective effects in the vasculature.

Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease

“…Homocysteine-induced expression of MCP-1 and IL-8 has been shown to occur through activation of NF-kB, a transcription factor known to stimulate the production of cytokines, chemokines, leukocyte adhesion molecules, and hemopoetic growth factors -all of which are thought to contribute to vascular inflammation and atherogenesis. [1][2][3] The recent observations that NF-kB activation and downstream proinflammatory mediators and cytokines are increased in atherosclerotic lesions from hyperhomocysteinemic apolipoprotein E-deficient mice 28,62 further supports the concept that HHcy accelerates atherogenesis by causing vascular inflammation.…”

“…[25][26][27][28] Transgenic mice deficient in CBS or MTHFR have also been used as animal models of HHcy. Homozygous CBS-deficient mice have total plasma homocysteine levels 40-fold greater than normal and suffer from severe growth retardation, hepatic steatosis, and dislocation of the lens 109 -phenotypic changes also observed in human patients with homocystinuria.…”

“…Several recent studies have demonstrated that mild HHcy accelerates atherogenesis in apoE-deficient mice. [25][26][27][28] Zhou et al 25,26 demonstrated that apoE-deficient mice fed chow diets supplemented with either methionine or homocysteine developed larger, more complex and more numerous arterial lesions, compared to mice fed control diets (Figure 3). Lesions were rich in smooth muscle cells and collagen, a result consistent with the ability of homocysteine to stimulate SMC proliferation and extracellular matrix deposition.…”

“…24 Furthermore, a direct causal relationship between induction of HHcy and accelerated atherosclerosis has been reported in apolipoprotein E (apoE)-deficient mice with diet-and/or genetic-induced HHcy. [25][26][27][28] Given that oral administration of folic acid or a combination of B vitamins can decrease HHcy and attenuate atherogenesis in these animal models, 26,28 there is growing interest for treatment of HHcy as a strategy for prevention of atherothrombotic disease.…”

Epigenetic modifications and human pathologies: cancer and CVD

“…Generally, hyperhomocysteinemia is associated with a 2-fold increase in aortic plaque area (74)(75)(76) but vitamin B deficiency is not (74,77) . Conversely, vitamin B supplementation (up to three times control levels in the diet) is reported to decrease endogenous and homocysteine-induced plaque formation in ApoE null mice (74,76) . However, the data are inconsistent and profoundly dependent on the dietary regimen (74,76) .…”