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

Abstract

Recent studies suggest that some of the beneficial effects of 3-hydroxyl-3-methylglutaryl (HMG)-CoA reductase inhibitors such as pravastatin may be through their cholesterol-lowering independent effects on the blood vessels. We have recently reported that chronic inhibition of nitric oxide (NO) synthesis with NWnitro-L-arginine methyl ester (L-NAME) increases systolic blood pressure and induces coronary vascular inflammatory changes in rats. We designed this study to investigate whether treatment with pravastatin attenuates such proarteriosclerotic changes through their cholesterol-lowering independent effects.Several groups of Wistar-Kyoto rats were studied: the control group, L group received L-NAME in their drinking water (100 mg/kg per day) and L+Px group received L-NAME plus pravastatin (50, 100 or 250 mg/kg per day). We observed marked increases in monocyte infiltration into the coronary arteries, proliferative cell nuclear antigen-positive cells, and monocyte chemoattractant protein-1 (MCP-1) expression in the heart on day 3 after L-NAME administration began. Treatment with pravastatin did not affect serum cholesterol levels or systolic blood pressure but did reduce the L-NAME induced inflammatory and proliferative changes. Pravastatin also attenuated the MCP-1 gene expression induced by L-NAME. In summary, pravastatin inhibited the inflammatory and proliferative changes in the coronary vessels through their cholesterol-independent effects in this model, which may provide an insight into the mechanisms of antiinflammatory or anti-arteriosclerotic actions of pravastatin. (Hypertens Res 2000; 23: 353-358)

Ezetimibe in Combination With Statins Ameliorates Endothelial Dysfunction in Coronary Arteries After Stenting

“…Statins have direct effects on vascular endothelium that enhance the NO pathway [25][26][27] in addition to lipid-lowering effects; however, the clinical importance of this pleiotropic effect of statins is not yet firmly established. Endothelial dysfunction in hypercholesterolemia is attributed primarily to oxidized LDL, which has been shown to decrease NO bioavailability in endothelial cells through the inhibition of the expression of NO synthase 28 and the production of reactive oxygen species via the lectin-like oxidized LDL receptor (LOX-1).…”

Clinical Importance of Endothelial Function in Arteriosclerosis and Ischemic Heart Disease

“…55 In the early stages (day 3-7) of long-term NO synthesis inhibition, there aere marked inflammatory (adhesion and infiltration of monocytes) and proliferative (appearance of proliferating cell nuclear antigen-positive cells) changes in the blood vessels, especially the coronary arteries. 55 Simultaneously, there is (1) increases in tissue angiotensin-converting enzyme (ACE) and angiotensin type I receptor, resulting in an increase in AII activity; 53,54,56 (2) increased gene and protein expression of chemokines such as MCP-1, 55,57 and cytokines such as transforming growth factor-(TGF-), tissue factor etc); [58][59][60] and (3) increased production of superoxide anions ensuring oxidative stress, and increased activities of transcription factors (NF-B and AP-1). 61,62 All of these pathophysiologic and pathobiologic changes are probably the result of NO synthesis inhibition, but do not result from nonspecific actions of L-NAME, because (1) normalization of L-NAME-induced hypertension by treatment with hydralazine does not have an effect; 53,54 (2) restoration of NO synthesis by co-administration of L-arginine prevents L-NAME-induced pathologic changes; 55 and (3) administration of D-NAME does not cause hypertension or pathologic changes.…”

Lipoxygenase Products Regulate Nitric Oxide and Inducible Nitric Oxide Synthase Production in Interleukin-1.BETA. Stimulated Vascular Smooth Muscle Cells.

“…In VSMCs, IL-1β not only induces extion of NO with the superoxide anion. Therefore, regulation of iNOS gene expression has also been implicated in the pathogenesis of vascular remodeling and atherosclerosis (8)(9)(10)(11). Recently, the significance of iNOS in the pathogenesis of atherosclerosis was demonstrated by studies of genetic deficiency of iNOS in apo E-gene deficient mice (12).…”