Abstract
S-adenosylhomocysteine (SAH) is a risk factor of cardiovascular diseases and atherosclerosis. However, the causal association between SAH and atherosclerosis is still uncertain. In the present study, heterozygous SAH hydrolase (SAHH+/−) knockout mice were bred with apolipoprotein E-deficient mice to produce ApoE−/−/SAHH+/− mice. At 8 weeks of age, these mice were fed on AIN-93G diets added with or without betaine (4 g betaine/100 g diet) for 8 weeks. Compared with ApoE−/−/SAHHWT mice, SAHH deficiency caused an accumulation of plasma SAH concentration and a decrease in S-adenosylmethionine (SAM)/SAH ratio as well as plasma homocysteine levels. Betaine supplementation lowered SAH levels and increased SAM/SAH ratio and homocysteine levels in ApoE−/−/SAHH+/− mice. Furthermore, SAHH deficiency promoted the development of atherosclerosis, which was reduced by betaine supplementation. The atheroprotective effects of betaine on SAHH-deficiency-promoted atherosclerosis were associated with inhibition of NFκB inflammation signaling pathway and inhibition of proliferation and migration of smooth muscle cells. In conclusion, our results suggest that betaine supplementation lowered plasma SAH levels and protected against SAHH-deficiency-promoted atherosclerosis through repressing inflammation and proliferation and migration of smooth muscle cells.
Highlights
Cardiovascular disease (CVD) is the world’s leading killer
NF-κB can directly regulate a variety of genes overexpression, participating in the initiation and progression of atherosclerotic lesions, such as monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1), which result in the adhesion of monocytes to endothelial cells and proliferation and migration of vascular smooth muscle cells (VSMCs), and promote the occurrence and development of atherosclerosis [6,7]
At 8 weeks of age, ApoE−/−/SAH hydrolase (SAHH)+/− mice and their littermate ApoE−/−/SAHHWT mice were fed with AIN-93G diets with or without added betaine (4 g betaine/100 g diet) for 8 weeks
Summary
Cardiovascular disease (CVD) is the world’s leading killer. Atherosclerosis is among the leading causes of CVD, myocardial infarction, and stroke worldwide. It is known that migration and proliferation of vascular smooth muscle cells (VSMCs) are key processes in the neointima formation that occurs during atherosclerosis [1]. MAPKs activation, such as ERK1/2, are widely known as the main molecules responsible for initiating the signaling pathway involved in VSMCs proliferation, migration, and growth [3]. NF-κB has been proposed to be an integrator of many process that affect the formation of atherosclerosis plaques, and its activation represents a key mechanism that regulates various inflammatory and immune responses [5]. NF-κB can directly regulate a variety of genes overexpression, participating in the initiation and progression of atherosclerotic lesions, such as monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1), which result in the adhesion of monocytes to endothelial cells and proliferation and migration of VSMCs, and promote the occurrence and development of atherosclerosis [6,7]. It is unclear how to effectively reduce the plasma level of SAH and whether lowering plasma levels of SAH could prevent atherosclerosis
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