Effects of Folic Acid and Magnesium on the Production of Homocysteine-Induced Extracellular Matrix Metalloproteinase-2 in Cultured Rat Vascular Smooth Muscle Cells

Abstract

igration of vascular smooth muscle cells (VSMCs) into the vascular intima and their subsequent proliferation and remodeling of the extracellular matrix are important events in the pathogenesis of atherosclerosis. These events are regulated by various cytokines and growth factors secreted by platelets and vascular cells. 1 Zempo et al reported that the processes of migration and proliferation of VSMCs that contribute to the morphogenesis of atherosclerotic plaque require extracellular matrix remodeling induced by matrix metalloproteinases (MMPs). 2 Brown et al identified MMPs in human coronary atherosclerotic lesions and suggested that MMPs are closely related to the progression of atherosclerosis. 3 Homocysteine is an intermediate sulfur-containing amino acid formed during the intracellular metabolism of methionine. Circulating homocysteine can be increased by a genetic deficiency of the enzymatic pathways involved in Circulation Journal Vol.70, January 2006 its catabolism, as well as by environmental factors including nutritional deficiencies, life style, physiological conditions, drugs and some diseases, which mainly induce a deficiency of folic acid and vitamins B12 and B6. Therefore, the plasma homocysteine level can be reduced by interventional therapy with folic acid and vitamin B12. 4 Hyperhomocysteinemia is an independent risk factor for coronary artery disease (CAD). 5 Magnesium has been implicated in the negative correlation between cardiovascular disease and hardness of drinking water. 6 Dietary deficiency of magnesium augmented atherogenesis markedly in experimental animals fed a high cholesterol diet, and oral supplementation of magnesium to the same animals lowered serum lipid levels and attenuated the atherosclerotic process. 7 Our previous studies demonstrated that the magnesium status of men and women with variant angina is closely related to disease activity and that the intracellular magnesium level decreased in patients with cardiac syndrome X. 8-10 However, Liao et al indicated that the association of low serum and dietary magnesium with the incidence of coronary heart disease may not be causal, because the results of their prospective study differed between men and women. 11 However, the effects of magnesium, which is a natural calcium antagonist, and folic acid on homocysteine-in- Effects of Folic Acid and Magnesium on the Production of Homocysteine-Induced Extracellular Matrix Metalloproteinase-2 in Cultured Rat Vascular Smooth Muscle CellsHangyuan Guo, MD, PhD* , **; Jong-Dae Lee, MD**; Hiroyasu Uzui, MD**; Hong Yue, MD**; Junbo Wang, MD**; Kiyohiro Toyoda, MD**; Tooru Geshi, MD**; Takanori Ueda, MD** Background Hyperhomocysteinemia is an independent risk factor of coronary artery disease, but some studies have shown that patients with hyperhomocysteinemia are not prone to atherosclerosis. The aim of this study was to test whether homocysteine increases the production of matrix metalloproteinase-2 (MMP-2) and if extracellular additional magnesium and folic acid alters MMP-2 secreti...

Relationship Between Plasma Homocysteine Levels and Congestive Heart Failure in Patients With Acute Myocardial Infarction Homocysteine and Congestive Heart Failure

“…[3][4][5][6][7][8][9][10][11][12][13][14] Many issues regarding the mechanism of action of homocysteine in the pathogenesis of arteriosclerosis and thrombotic diseases remain unclear. However, possible causes include vascular endothelial dysfunction, [17][18][19][20][21][22] smooth muscle cell growth, [23][24][25] and an increase in blood clotting activity in vascular walls. 26,27) Elevated homocysteine levels may promote heart failure through 4 potential mechanisms.…”

Matrix metalloproteinases-2, -3 and tissue inhibitors of metalloproteinases-1, -2 in placentas from preterm pregnancies and their association with one-carbon metabolites

“…We have recently reported increased placental levels of MMP1 (collagenase) and MMP9 (gelatinase) in women delivering preterm (Sundrani et al 2012). The activity of MMPs is reported to be regulated by homocysteine, oxidative stress, and long-chain polyunsaturated fatty acids (LCPUFA; Guo et al 2006, Kundu et al 2009, Solakivi et al 2009, Zainal et al 2009, Zeydanli & Turan 2009, Ke et al 2010.…”

In vivo evaluation of Mg–6Zn and titanium alloys on collagen metabolism in the healing of intestinal anastomosis

“…In another frontier study, the researchers hypothesized that Mg ion released from corroded Mg screws blocked MMP-13 expression, inhibited the degradation of collagens via tyrosine kinase inhibitors through a highlighted signaling pathway41. In previous researches, it was demonstrated that extracellular Mg reduced MMPs in a dose-dependent manner in cultured rat vascular smooth muscle cells as well as rat cardiac fibroblasts potentially via two tyrosine kinase inhibitors, genistein and herbimycin A4445. According to the hypothesis, it could be inferred that magnesium may have indirect effect on the inhibition of MMPs and suppressed the influence of magnesium on the expression of IL-6 and MMP-1 in vivo 46.…”