Alterations in the lipid profile and liver enzymes of rats treated with monosodium glutamate
Epidemiological studies strongly suggest an inverse correlation between plasma high-density lipoprotein (HDL) concentration and the risk of ischemic heart disease.1,2 Experimental evidence also exists to indicate cardioprotective effects of HDL.3 However, the mechanism for protective effect of HDL against ischemic heart disease is not completely understood. Although the widely accepted mechanism comprises the ability of HDL to enhance reverse cholesterol transport,4 cholesterol-independent mechanisms have also been postulated. For example, lower HDL is associated with endothelial cell injury, which is involved both in the progression of atherogenesis and myocardial ischemiareperfusion injury. The ability of HDL to inhibit endothelial adhesion molecule expression5 and to potentiate prostacyclin release from the endothelial cells6 further supports cholesterol-independent mechanism of HDL. Antiatherogenic property of HDL is mediated by its ability to release cholesterol from lipid-containing cells followed by esterification through lecithin:cholesterol acyltransferase and delivery to the liver and to steroidogenic organs for subsequent synthesis of bile acids and lipoproteins.7 Most importantly, HDL can inhibit oxidation of low-density lipoprotein (LDL) as well as the atherogenic effects of oxidized LDL by virtue of its antioxidant property. Atherosclerosis is an inflammatory disease characterized by adhesion of circulating monocytes to activated endothelial cells followed by migration to the subendothelium with the help of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin.8 Consistent with these reports, there is an increased expression of adhesion molecules in atherosclerotic plaque9 and upregulation of adhesion molecules in the acute thrombotic process.10 Recently, an increased plasma concentration of soluble adhesion molecules has been described as a risk factor for ischemic heart disease.11 The adhesion molecules are synthesized in the endothelial cells by the cytokines including interleukin-1 (IL-1) and tumor necrosis factor(TNF). An increased expression of TNFhas been reported in human atheroclerosis.12 A recent study showed protection of endothelial cells from TNF–induced apoptosis by HDL.13 In that study, the authors demonstrated that HDL prevented apoptosis of human umbilical venous endothelial cells (HUVECs) induced by TNFvia an inhibition of CPP32-like protease activity. The incubation of HUVECs with TNFsignificantly increased CPP32-like protease activity and induced apoptosis. Prostacyclin (PGI2), a vasodilator that contributes to the maintenance of vascular tone, may also function as an endogenous antiatherogenic molecule.14 The antiatherogenic property of PGI2 is attributed to its ability to inhibit platelet aggregation and adhesion and to block leukocyte activation and adhesion. Several reports exist in the literature indicating PGI2 release by HDL by a Cox-2–dependent mechanism although Cox-1 may also have some role.15 Cox-2 induction by HDL may be viewed as heart’s own effort to upregulate its own defense to limit the deleterious effects of ischemia and reperfusion. In this issue of Circulation Research, Calabresi et al16 reported HDL protection of isolated rat hearts from ischemia/ reperfusion injury by a mechanism that involves reduction of cardiac TNFand enhancement of prostaglandin release. Preperfusion of the isolated hearts with HDL improved postischemic functional recovery and reduced creatine kinase release from the heart indicating cardioprotective effects of HDL. These results were corroborated by a reduction in the ischemia-induced expression of TNFand enhancement of prostaglandin release. The rate-limiting enzyme for the prostaglandin synthesis is cyclooxygenase, which is present in two different forms. Cyclooxygenase-1 (Cox-1) is ubiquitously present in many tissues, whereas cyclooxygenase-2 (Cox-2) is usually absent in the cells, but induced upon stimulation by agents like cytokines and mitogens.17 A recent study demonstrated that HDL could induce PGI2 release in Cox-2–dependent manner and that its synthesis is regulated by both transcriptional and translational machineries.15 The study showed several-fold increase in HDL-induced release of PGI2, which was blocked by a selective Cox-2 inhibitor, (N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide). Cycloheximide, actinomycin D, and dexamethasone downregulated HDL-induced PGI2 synthesis, suggesting de novo synthesis of protein and mRNA of Cox-2 by HDL. HDL can differentially modulate cytokine-induced expression of E-selectin and Cox-2.18 Preincubation with HDL completely abolished E-selectin expression in the endothelial cells in response to TNF. Transient cotransfection experiments determined that HDL could inhibit cytokine-induced expression of a reporter gene driven by the E-selectin proximal promoter. HDL did not influence the nuclear translocation or DNA binding of NFB or alter the kinetics of degradation and resynthesis of the inhibitory protein I B . The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington, Conn. Correspondence to Dipak K. Das, PhD, Cardiovascular Research Center, University of Connecticut, School of Medicine, Farmington, CT 06030-1110. E-mail firstname.lastname@example.org (Circ Res. 2003;92:258-260.) © 2003 American Heart Association, Inc.