Cerivastatin ameliorates high insulin-enhanced neutrophil–endothelial cell adhesion and endothelial intercellular adhesion molecule-1 expression by inhibiting mitogen-activated protein kinase activation

• Published in: Journal of diabetes and its complications Vol. 17; no. 6; pp. 380 - 386
• Main Authors: Okouchi, Masahiro, Okayama, Naotsuka, Omi, Hitoshi, Imaeda, Kenro, Shimizu, Manabu, Fukutomi, Tatsuya, Itoh, Makoto
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.11.2003; Elsevier Science; Elsevier Limited
• Subjects: Atherosclerosis; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Biosynthesis; Blood and lymphatic vessels; Cardiology. Vascular system; Cell adhesion & migration; Cell Adhesion - drug effects; Cell culture; Diabetes; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Enzyme Inhibitors - pharmacology; Enzymes; Heart attacks; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Hyperinsulinemia; Hyperinsulinism - metabolism; Hyperinsulinism - physiopathology; In Vitro Techniques; Insulin; Insulin - pharmacology; Insulin resistance; Intercellular Adhesion Molecule-1 - drug effects; Intercellular Adhesion Molecule-1 - metabolism; Kinases; Lipids; Medical sciences; Mevalonic Acid - metabolism; Mitogen-Activated Protein Kinases - drug effects; Mortality; Neutrophils - drug effects; Neutrophils - metabolism; Protein Kinase C - drug effects; Proteins; Pyridines - pharmacology; Rodents; Signal Transduction - drug effects; Umbilical Cord - cytology; Vascular inflammation; Japan; Hyperinsulinemia; Insulin resistance; Diabetes; Vascular inflammation; Atherosclerosis; Endocrinopathy; Endothelial cell; Granulocyte; Cardiovascular disease; Activation; Cerivastatin; Vascular disease; Ηyperinsulinemia; Blood vessel; Intercellular adhesion molecule 1; Enzyme; Diabetes mellitus; Cell adhesion molecule; Enzyme inhibitor; Mitogen-activated protein kinase; Statin derivative; Inflammation; Adhesion; Insulin; Target tissue resistance; Hydroxymethylglutaryl-CoA reductase; Oxidoreductases; Neutrophil; Antilipemic agent
• ISSN: 1056-8727; 1873-460X
• DOI: 10.1016/S1056-8727(02)00245-3

There is growing evidence that hyperinsulinemia is linked to the development of atherosclerosis in patients with diabetes. We demonstrated previously that high insulin exacerbates neutrophil–endothelial cell adhesion and endothelial intercellular adhesion molecule (ICAM)-1 expression through activation of protein kinase C (PKC) and mitogen-activated protein (MAP) kinase. Though 3-hydroxymethyl-3-glutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have been employed as therapeutic agents in the treatment of dyslipidemia, which is frequently accompanied by diabetes mellitus; it is not known whether statins protect against leukocyte–endothelial interactions, especially in hyperinsulinemia. In this study, we determined which statin(s) could protect against endothelial reactions to high insulin. Studies of adhesion between neutrophils from healthy volunteers and human umbilical vein endothelial cells incubated in regular insulin-rich medium with or without statins were performed. Adhered neutrophils were quantified by measuring their myeloperoxidase (MPO) activities, and endothelial expression of ICAM-1 was examined using an enzyme immunoassay. Both the increased neutrophil–endothelial cell adhesion and ICAM-1 expression caused by high insulin (100 μU/ml) for 48 h were significantly attenuated by pretreatment with cerivastatin (0.01 μM), but not by fluvastatin (0.5 μM) or pravastatin (0.05 μM). These protective actions of cerivastatin were attenuated by a key intermediate in the cholesterol biosynthesis pathway, mevalonate (400 μM). In addition, cerivastatin attenuated both neutrophil–endothelial cell adhesion and endothelial ICAM-1 expression enhanced by a MAP kinase activator, anisomycin (1 μM) but not by a PKC activator, PMA (10 nM). These results suggest that through inhibiting MAP kinase but not PKC activation therapy with cerivastatin would be promising strategy for inhibiting neutrophil–endothelial cell adhesion and endothelial ICAM-1 expression enhanced by high insulin, which is closely correlated with atherosclerosis.