Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, or statins, are effective lipid-lowering agents, extensively used in medical practice. Statins have never been shown to be involved in the immune response, although a report has indicated a better outcome of cardiac transplantation in patients under Pravastatin therapy. Major histocompatibility complex class II (MHC-II) molecules are directly involved in the activation of T lymphocytes and in the control of the immune response. Whereas only a limited number of specialized cell types express MHC-II constitutively, numerous other cells become MHC-II positive upon induction by interferon gamma (IFN-gamma). This complex regulation is under the control of the transactivator CIITA (refs 6,7). Here we show that statins act as direct inhibitors of induction of MHC-II expression by IFN-gamma and thus as repressors of MHC-II-mediated T-cell activation. This effect of statins is due to inhibition of the inducible promoter IV of the transactivator CIITA and is observed in several cell types, including primary human endothelial cells (ECs) and monocyte-macrophages (Mstraight phi). It is of note that this inhibition is specific for inducible MHC-II expression and does not concern constitutive expression of CIITA and MHC-II. In repressing induction of MHC-II, and subsequent T-lymphocyte activation, statins therefore provide a new type of immunomodulation. This unexpected effect provides a scientific rationale for using statins as immunosuppressors, not only in organ transplantation but in numerous other pathologies as well.

Abstract-Increasing evidence supports the involvement of inflammation in the early phases of atherogenesis. Recruitment of leukocytes within the vascular wall, controlled by chemokines, is an essential process in the development of this common disease. In this study, we report that blocking a chemokine pathway in vivo with the CC chemokine antagonist Met-RANTES reduces the progression of atherosclerosis in a hypercholesterolemic mouse model. The reduction of lesions was correlated with a diminution of expression of several major chemokines and chemokine receptors, a decrease in leukocyte infiltration, and an increase of collagen-rich atheroma, features associated with stable atheroma. Treatment was well tolerated and serum lipid profiles were not affected. Whereas genetically engineered mice with deletion of either a CC chemokine or its receptor have demonstrated resistance to disease, to our knowledge, this is the first demonstration that treatment with a chemokine receptor antagonist limits the progression of atherosclerosis in vivo. Thus, our findings indicate that blockade of chemokine receptor/ligand interactions might become a novel therapeutic strategy to reduce the evolution of this common disease. A therosclerosis is an inflammatory disease characterized by arterial lesions containing cholesterol, immune infiltrates, and fibrosis, 1-3 resulting essentially from hyperlipidemia, hypertension, smoking, and diabetes. 4 These cardiovascular risk factors cause endothelial dysfunction, which triggers the migration of leukocytes, mainly of monocyte/ macrophage and T lymphocyte type, within the vessel wall intima area. Proinflammatory factors, such as cytokines and chemokines, released from endothelial cells (ECs), macrophages, or T cells, cause proliferation and migration of smooth muscle cells (SMCs) from the media to the intima, as well as recruitment of new immunoinflammatory cells. Within the intima, SMCs secrete extracellular matrix components, leading to the accumulation of collagen and proteoglycans, key factors implicated in plaque stability. Conversely, the secretion of matrix metalloproteinases by vascular and inflammatory cells degrades matrix components, such as collagen, gelatin, or elastin within atherosclerotic lesions.Chemokines (chemotactic cytokines) belong to a large superfamily of low molecular weight proteins with a highly homologous 3-dimensional structure, which are divided into four groups based on the configuration of the first two cysteines. 5,6 Chemokines are known to induce leukocyte migration, growth, and activation through 7 transmembrane heptahelical, G protein-coupled cell-surface receptors on target cells and regulate leukocyte trafficking during inflammation. The chemokine CCL5/RANTES (Regulated on Activated Normal T-Cell Expressed and Secreted) is a soluble chemokine of 7.8 kDa secreted by many different cell types, such as ECs, SMCs, activated T cells, macrophages, and platelets. 7,8 RANTES interacts with the chemokine receptors CCR1, CCR3, and CCR5, and has been implicated i...

Paracrine cell-to-cell interactions are crucial events during atherogenesis. However, little is known about the role of direct intercellular communication via gap junctions during this process. We have investigated the expression pattern of 3 vascular gap junction proteins (connexins) in mouse and human atherosclerotic plaques. Low density lipoprotein receptor-deficient mice were fed a high-fat diet for 0, 6, 10, or 14 weeks to induce different stages of atherosclerosis. Connexin37 (Cx37) and Cx40 were detected in the endothelium, and Cx43 was detected in the media of nondiseased aortas. In early atheromas, endothelial and medial connexin expression remained unchanged, and "islets" of Cx43 in smooth muscle cells and Cx37 in macrophages were observed in the neointima. In advanced atheromas, Cx37 was detected in medial smooth muscle cells and in macrophages in the lipid core but not in the endothelium covering the plaques. Cx40 could also no longer be detected in the endothelium covering the plaques. Cx43, on the other hand, was detected in the endothelium covering the shoulder of the plaques and also sparsely in neointimal smooth muscle cells. Similar results were obtained for human carotid arteries. In conclusion, vascular connexins are differentially expressed by atheroma-associated cells within lesions. These observations suggest a role for gap junctional intercellular communication during atherogenesis.

Background— Gap junctions allow the direct exchange of ions and small molecules between cells in contact, thus coordinating physiological processes such as cell growth and differentiation. We have recently demonstrated increased expression of the gap junction protein connexin43 (Cx43) in specific subsets of cells in atherosclerotic lesions. Because the development of atherosclerosis depends critically on paracrine cell-to-cell interactions, we hypothesized that direct intercellular communication via gap junctions may be another factor controlling atherogenesis. Methods and Results— The role of Cx43 in atherogenesis was examined by use of both a genetic and a pharmacological approach. First, atherosclerosis-susceptible LDL receptor–deficient (LDLR −/− ) mice with normal (Cx43 +/+ ) or reduced (Cx43 +/− ) levels of Cx43 were fed a cholesterol-rich diet for 14 weeks. The progression of atherosclerosis was reduced by 50% ( P <0.01) in the thoracoabdominal aorta and in the aortic roots of Cx43 +/− LDLR −/− mice compared with Cx43 +/+ LDLR −/− controls. Atheroma in Cx43 +/− LDLR −/− mice contained fewer inflammatory cells and exhibited thicker fibrous caps with more collagen and smooth muscle cells. Next, we observed that HMG-CoA reductase inhibitors, or “statins,” lipid-lowering drugs well known for their pleiotropic antiatherogenic effects, reduced Cx43 expression in primary human vascular cells in vitro. Atheroma of LDLR −/− mice treated orally with pravastatin contained fewer inflammatory cells and exhibited thicker fibrous caps than controls. This was associated with reduced Cx43 expression in lesions of statin-treated mice. Conclusions— These data indicate a critical role for Cx43-mediated gap junctional communication in atherosclerotic plaque formation.

Statins decrease CD40 expression and CD40-related activation of vascular cells. These effects are partially reversed by the HMG-CoA reductase product L-mevalonate and are mediated by NOS- or PPAR-dependent pathways. Altogether, these findings provide mechanistic insight into the beneficial effects of statins on atherogenesis. They also provide a scientific rationale for the use of statins as immunomodulators after organ transplantation.