Background:Mn 2ϩ levels are lower in blood of diabetic and atherosclerosis patients. Results: Mn 2ϩ supplementation reduces monocyte adhesion in endothelial cells by down-regulating ROS, ICAM-1 expression, and MCP-1 secretion, and lowers blood levels of ICAM-1 and cholesterol in ZDF rats.
Conclusion:Mn 2ϩ supplementation is beneficial in lowering markers of endothelial dysfunction. Significance: Mn 2ϩ supplementation can potentially prevent or delay progression of atherosclerosis.Endothelial dysfunction is a hallmark of increased vascular inflammation, dyslipidemia, and the development of atherosclerosis in diabetes. Previous studies have reported lower levels of Mn 2؉ in the plasma and lymphocytes of diabetic patients and in the heart and aortic tissue of patients with atherosclerosis. This study examines the hypothesis that Mn 2؉ supplementation can reduce the markers/risk factors of endothelial dysfunction in type 2 diabetes. Human umbilical vein endothelial cells (HUVECs) were cultured with or without Mn 2؉ supplementation and then exposed to high glucose (HG, 25 mM) to mimic diabetic conditions. Mn 2؉ supplementation caused a reduction in monocyte adhesion to HUVECs treated with HG or MCP-1. Mn 2؉ also inhibited ROS levels, MCP-1 secretion, and ICAM-1 up-regulation in HUVECs treated with HG. Silencing studies using siRNA against MnSOD showed that similar results were observed in MnSOD knockdown HUVECs following Mn 2؉ supplementation, suggesting that the effect of manganese on monocyte adhesion to endothelial cells is mediated by ROS and ICAM-1, but not MnSOD. To validate the relevance of our findings in vivo, Zucker diabetic fatty rats were gavaged daily with water (placebo) or MnCl 2 (16 mg/kg of body weight) for 7 weeks. When compared with placebo, Mn 2؉ -supplemented rats showed lower blood levels of ICAM-1 (17%, p < 0.04), cholesterol (25%, p < 0.05), and MCP-1 (28%, p ؍ 0.25). These in vitro and in vivo studies demonstrate that Mn 2؉ supplementation can down-regulate ICAM-1 expression and ROS independently of MnSOD, leading to a decrease in monocyte adhesion to endothelial cells, and therefore can lower the risk of endothelial dysfunction in diabetes.Manganese is an essential micronutrient that serves as a cofactor for many enzyme systems. Metalloenzymes, or manganese-containing enzymes, such as arginase, pyruvate carboxylase, and manganese superoxide dismutase (MnSOD), 2 require Mn 2ϩ to function. MnSOD is the major mitochondrial antioxidant and is responsible for protecting the cell from reactive oxygen species (ROS) by scavenging mitochondrial superoxide (1). MnSOD acts by catalyzing the conversion of superoxide radicals (such as O 2 ) to hydrogen peroxide, which is further metabolized to water by other antioxidant enzymes such as catalase and glutathione peroxidase (2). At low concentrations, Mn 2ϩ ions have been shown to have antioxidant properties with the ability to scavenge superoxide and hydroxyl radicals (3). Several studies have reported that changes in dietary Mn 2ϩ induced changes in MnS...