title: Manganese supplementation reduces high glucose-induced monocyte adhesion to endothelial cells and endothelial dysfunction in Zucker diabetic fatty rats.
abstract: 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 MnCl2 (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.
authors: Department of Pediatrics and Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130, USA.
authors: Elodie
authors: E
authors: Burlet
authors: Sushil K
authors: SK
authors: Jain
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D018932:Chemokine CCL2 / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D008345:Manganese / Q000494:pharmacology*; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D011924:Rats, Zucker; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D013549:Sweetening Agents / Q000494:pharmacology*
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D017382:Reactive Oxygen Species; D013549:Sweetening Agents; D018799:Intercellular Adhesion Molecule-1; D008345:Manganese; D013482:Superoxide Dismutase; D005947:Glucose