Mevalonate-Dependent Inhibition of Transendothelial Migration and Chemotaxis of Human Peripheral Blood Neutrophils by Pravastatin

Abstract

Pravastatin, a hydrophilic inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, has been reported to beneficially affect atherogenesis, plaque stability, and transient myocardial ischemia in significant coronary artery disease by influencing lipid metabolism and by intracellular signaling via mevalonate pathway products other than cholesterol. Leukocytes are implicated to play a pathophysiological role in these events. We were interested in finding out whether pravastatin could affect transendothelial migration (TEM), chemotaxis, and respiratory burst activity of the neutrophil ex vivo. In addition, effects on monocyte and T-lymphocyte chemotaxis were tested. For TEM assays, monolayers of human umbilical vein endothelial cells (HUVECs) were grown to confluence on polycarbonate filters bearing 5-microns pores in Transwell (Costar) culture plate inserts. Chemotaxis experiments were performed using modified Boyden chambers with cellulose nitrate micropore filters. Respiratory burst activity was measured fluorometrically. Treatment of neutrophils and monocytes with pravastatin at 2 to 200 mumol/L and 10 to 1000 mumol/L, respectively, significantly decreased chemotaxis triggered by fMet-Leu-Phe. This effect was abolished in the presence of mevalonic acid (500 mumol/L); no effect of pravastatin was seen on T-lymphocyte chemotaxis triggered by interleukin-8. Preincubation of neutrophils with pravastatin (200 mumol/L) also resulted in a significant reduction in the number of neutrophils that transmigrated a tumor necrosis factor-stimulated or lipopolysaccharide-stimulated HUVEC monolayer. At none of the concentrations tested (2 pmol/L to 200 mumol/L) did pravastatin affect neutrophil respiratory burst activity. We conclude that pravastatin may alter monocyte chemotaxis and neutrophil-endothelial interactions in migratory responses at concentrations obtained in vivo with cholesterol-lowering doses.

The HMG-CoA reductase inhibitor rosuvastatin and the angiotensin receptor antagonist candesartan attenuate atherosclerosis in an apolipoprotein E-deficient mouse model of diabetes via effects on advanced glycation, oxidative stress and inflammation

“…While a reduction in LDL-cholesterol was observed in many of these studies, it is now considered that statins also mediate pleiotropic antiatherogenic effects that are independent of their effects on lipoproteins, and that this action may contribute to their efficacy in reducing cardiovascular events. Indeed, HMGCoA reductase inhibitors have been shown to attenuate, although not in the context of diabetes, many of the stages critical to atherosclerotic plaque development including monocyte chemotaxis [13], neutrophil-endothelial cell interaction [13], smooth muscle cell apoptosis [14], migration [15] and proliferation [16], as well as plaque stability [17].…”

High insulin enhances neutrophil transendothelial migration through increasing surface expression of platelet endothelial cell adhesion molecule-1 via activation of mitogen activated protein kinase

“…In addition, recent reports suggested that neutrophils were occasionally found in disrupted plaques [11], and myeloperoxidase (MPO), the enzyme of leukocytes (including neutrophils) which promotes oxidation of lipoproteins, was present in atherosclerotic plaques [12]. These observations support the importance of neutrophil transendothelial migration in the development and disruption of atherosclerotic plaques [13]. Therefore, we focused on the correlation between hyperinsulinaemia and neutrophil transendothelial migration.…”

“…In addition, endothelial migration of PMN obtained from diabetic patients with hyperinsulinaemia was also increased compared with that from healthy subjects. The PMN transendothelial migration enhanced by high insulin might account for the high incidence of atherosclerotic diseases such as AMI and stroke in patients with diabetes, because PMN transendothelial migration seems to contribute to the formation of atherosclerotic plaques and their disruption [4,13]. There is growing evidence supporting a close relation between atherosclerosis and PMN activation and migration [11,12,22,23,24,25,26,27].…”

Pravastatin Attenuates Cardiovascular Inflammatory and Proliferative Changes in a Rat Model of Chronic Inhibition of Nitric Oxide Synthesis by Its Cholesterol-Lowering Independent Actions.

“…For example, HMG-CoA reductase inhibitors such as pravastatin have been shown to inhibit chemotactic migration of monocytes (17) and neutrophils (18) in vitro. Treatment with pravastatin has been shown to reduce the number of monocytes infiltrated into atherosclerotic plaques (19,20) and to reduce metalloproteinase activity (21,22).…”