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


METHODS
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.


RESULTS
Both the increased neutrophil-endothelial cell adhesion and ICAM-1 expression caused by high insulin (100 microU/ml) for 48 h were significantly attenuated by pretreatment with cerivastatin (0.01 microM), but not by fluvastatin (0.5 microM) or pravastatin (0.05 microM). These protective actions of cerivastatin were attenuated by a key intermediate in the cholesterol biosynthesis pathway, mevalonate (400 microM). In addition, cerivastatin attenuated both neutrophil-endothelial cell adhesion and endothelial ICAM-1 expression enhanced by a MAP kinase activator, anisomycin (1 microM) but not by a PKC activator, PMA (10 nM).


CONCLUSIONS
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.
First Department of Internal Medicine, Nagoya City University Medical School, 1 Kawasumi, Mizuho-cho, Mizuho-ku, 467-8601, Nagoya, Japan. okochi@med.nagoya-cu.ac.jp
Masahiro
M
Okouchi
Naotsuka
N
Okayama
Hitoshi
H
Omi
Kenro
K
Imaeda
Manabu
M
Shimizu
Tatsuya
T
Fukutomi
Makoto
M
Itoh
D002448:Cell Adhesion / Q000187:drug effects*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D006946:Hyperinsulinism / Q000378:metabolism / Q000503:physiopathology*; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects / Q000378:metabolism; D008798:Mevalonic Acid / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects*; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D011493:Protein Kinase C / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014470:Umbilical Cord / Q000166:cytology
D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007328:Insulin; D011725:Pyridines; D018799:Intercellular Adhesion Molecule-1; C086276:cerivastatin; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D008798:Mevalonic Acid