Interleukin-10 blocks atherosclerotic events in vitro and in vivo.

Atherosclerosis can be viewed in part as an inflammatory disease process and may therefore be susceptible to manipulation of the immune state. Interleukin 10 (IL-10) is an inhibitory cytokine produced by activated lymphocytes and monocytes. These studies present evidence that IL-10 can inhibit minimally oxidized LDL (MM-LDL)-induced monocyte-endothelium interaction as well as inhibit atherosclerotic lesion formation in mice fed an atherosclerotic diet. Pretreatment of human aortic endothelial cells (HAECs) for 18, but not 4, hours with recombinant IL-10 caused a significant decrease in MM-LDL-induced monocyte binding. IL-10 was found to be maximally effective at 10 ng/mL. Transfection of HAECs with adenovirus expressing viral bcrf-1 IL-10 (Ad-vIL-10) in a sense but not antisense orientation completely inhibited the ability of MM-LDL to induce monocyte binding. Similar results were obtained with IL-10 or Ad-vIL-10 in HAECs stimulated with oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC). We have previously shown increases in cAMP associated with MM-LDL activation of endothelial cells. The MM-LDL-induced increase in cAMP levels was not inhibited by preincubation with IL-10. In vivo studies demonstrated that mice with a murine IL-10 transgene under the control of the human IL-2 promoter have decreased lesions versus controls on an atherogenic diet (5433+/-4008 mm(2) versus 13 574+/-4212 mm(2); P<0.05), whereas IL-10 null mice have increased lesions (33 250+/-9117 mm(2); P<0.0001) compared with either controls or IL-10 transgenic mice. These studies suggest an important role for IL-10 in the atherosclerotic disease process.

Association between serum amyloid A proteins and coronary artery disease: evidence from two distinct arteriosclerotic processes.

BACKGROUND: Serum amyloid A (SAA) proteins are a family of inflammatory apolipoproteins that may modify high-density lipoprotein structure and function. Elevations of SAA have been reported in unstable coronary syndromes, but the levels and types of SAA protein in humans with spontaneous or transplant-associated coronary artery disease are not known. METHODS AND RESULTS: SAA levels were analyzed using an ELISA in 76 sera from 36 patients after cardiac transplantation and in 346 other individuals, 85 patients with atherosclerotic coronary disease plus 261 of their relatives. The mean SAA level was 5-fold higher in transplant patients (203+/-181 microg/mL [23 to 934 microg/mL]) compared with normal subjects without coronary disease (36+/-16 microg/mL [2.8 to 193 microg/mL], P<.005). The mean SAA level was significantly elevated in patients with transplant coronary disease (206+/-160 microg/mL, n=23) compared with those without (140+/-104 microg/mL, n=12, P=.02). Elevated SAA levels were associated with increased mortality after transplantation. On multiple regression analysis, SAA levels were predicted by corticosteroid dose, pretransplant diagnosis of atherosclerotic coronary artery disease, and the presence of transplant coronary disease. SAA levels were elevated in patients with spontaneous atherosclerotic coronary disease (49+/-31 microg/mL) compared with unaffected relatives (39+/-36 microg/mL, mean+/-SD, P=.02). There was no evidence for a genetic contribution to SAA levels. All inducible human SAA protein types were documented by immunoblotting in both spontaneous and transplant coronary disease. CONCLUSIONS: Environmentally determined elevations in SAA levels in patients with both spontaneous and transplant coronary artery disease provide further evidence for a potential pathophysiological link between inflammation, lipoprotein metabolism, and the development of atherosclerosis.

Immunosuppressive agents and endothelial repair. Prednisolone delays migration and cytoskeletal rearrangement in wounded porcine aortic monolayers.

Endothelial denudation at areas of predilection to atherosclerosis is balanced by an active repair process that may be inhibited under conditions of accelerated atherosclerosis. After cardiac transplantation, the accelerated atherosclerotic process that develops may be enhanced by immunosuppressive agents that have nonspecific effects on cell signaling, proliferation, and response to injury. To study subtle effects of cyclosporine A, azathioprine, and 6 alpha-methylprednisolone on normal endothelial repair processes, confluent porcine endothelial monolayers were denuded in the presence of clinically relevant concentrations of these agents. The rate of endothelial wound repair was compared and the effects on cell spreading, proliferation, and the cytoskeleton assessed. 6 alpha-Methylprednisolone at concentrations of 1.25 to 50 mumol/L was associated with a transient 30% to 60% inhibition of endothelial wound repair. This was associated with increased cell size at the wound edge and a delay in centrosomal reorientation toward the wound, without any effect on cell proliferation. Cyclosporine and azathioprine in clinically relevant concentrations did not affect endothelial repair. Thus, corticosteroids transiently inhibit endothelial cytoskeletal alterations that are important in endothelial repair after a denuding injury.

Immune-deficient mice develop typical atherosclerotic fatty streaks when fed an atherogenic diet.

Inbred strain C57BL/6J mice develop typical atherosclerotic fatty streaks in the aorta after 15 wk on a high fat, high cholesterol diet. To investigate the effects of the immune system on the development of fatty streaks in this model, C57BL/6J mice with a normal immune system were compared with C57BL/6J mice carrying mutations resulting in various immune deficiencies. These included mice with severe combined immune deficiency, athymic "nude" mice, class I MHC deficient mice, and class II MHC deficient mice. Despite similar lipoprotein profiles, lesion development in the immune compromised strains was similar to or increased compared with normal C57BL/6J mice. Class I MHC deficient mice demonstrated a threefold increase in lesion area (22,961 +/- 6,653 vs 8,868 +/- 1,817 microns2, P = 0.01). Immunohistochemical analysis of lesions showed characteristic features of atherosclerosis with vascular cell adhesion molecule-1 expression, immunoglobulin deposition, monocyte infiltration, and smooth muscle cell proliferation. These data indicate that the classical immune system, while not essential for atherosclerotic fatty streak development, may act to suppress the development of lesions.

Recipient mononuclear cell recognition and adhesion to graft endothelium after human cardiac transplantation. Lymphocyte recognition leads to monocyte adhesion.

Transendothelial migration of mononuclear cells is crucial in the development of allograft rejection and transplant coronary disease. Adhesion of circulating cells to endothelium is the initial step in transendothelial migration. Human aortic endothelial cell cultures were established from aortic tissue harvested at the time of organ donation for cardiac transplantation which allowed specific recipient mononuclear cell-graft endothelial interactions to be studied. Confluent untreated endothelial cells were incubated with recipient mononuclear cells for 15 min to assess adhesion. Adhesion of recipient mononuclear cells to endothelium derived from their graft was threefold higher than adhesion to nonspecific endothelium (93 +/- 20 vs. 30 +/- 11 cells/high power field, P < 0.005). Graft-specific adhesion was inhibited by preincubation of the endothelium with antibodies to class I HLA (34 +/- 16 cells/high power field, P < 0.005). Immunofluorescence performed after adhesion showed that 73 +/- 6% of both specific and nonspecific adherent cells were monocytes. The use of purified lymphocyte and monocyte preparations showed that graft-specific lymphocytes induce unrelated monocytes to become adherent. These results suggest that lymphocytes are primed in vivo to recognize endothelium derived from their graft which leads to a rapid increase in lymphocyte and monocyte adhesion. Such allo-recognition may involve endothelial class I HLA molecules.

Antibodies to the T-cell receptor (CD3) induce LFA-1/Mac-1-dependent mononuclear cell adhesion to human arterial endothelium.

Monoclonal antibodies to the CD3 determinant on T lymphocytes have been used extensively as immunosuppressive agents. The T-cell receptor forms a complex with CD3 so that antibodies to CD3 mimic T-cell receptor cross-linking by human leukocyte antigens. Both CD3 and T-cell receptor cross-linking have been associated with lymphocyte activation and expression of the LFA-1 adhesion ligand, which leads to adhesion to intercellular adhesion molecule 1 immobilized on artificial surfaces. We sought to determine if anti-CD3 antibodies would increase adhesion of heart transplant recipient peripheral blood mononuclear cells to confluent human aortic endothelial cells by a similar mechanism. Peripheral blood mononuclear cells were incubated for 30 minutes with monoclonal CD3 or CD3 + CD18 antibody, before a 15-minute incubation with unstimulated human aortic endothelial cells. Mononuclear cell adhesion doubled after anti-CD3 antibody preincubation from 15.1 +/- 2.1 to 29.3 +/- 6.7 cells/high-power field (p = 0.002). This increase was abolished by coincubation with anti-CD18 (7.1 +/- 3 cells/high-power field; p = 0.0002). The major increase was the result of increased lymphocyte adhesion (3.4 +/- 0.6 to 14.8 +/- 6.7 cells/high-power field; p = 0.02); however, monocyte adhesion also increased from 11.7 +/- 1.5 to 14.5 +/- 1.6 cells/high-power field (p = 0.04). Anti-CD18 antibodies markedly reduced binding of both cell types. Cross-linking of the T-cell receptor by antibodies to CD3 causes acute adhesion of mononuclear cells (particularly lymphocytes) to arterial endothelium. Increased adhesion is mediated through CD18 (LFA-1/Mac-1).

Transplant atherosclerosis: the clinical syndrome, pathogenesis and possible model of spontaneous atherosclerosis.

OBJECTIVE: To summarize the clinical syndrome of transplant atherosclerosis, including the clinical risk factors, pathological features and known pathophysiological mechanisms. The review also examines transplant atherosclerosis and naturally occurring atherosclerosis to delineate common pathophysiological mechanisms and to promote transplant atherosclerosis as a model for the more commonly occurring spontaneous process. STUDY SELECTION: Information gathered includes studies related to transplantation, endothelium, atherosclerosis, macrophages, lipoproteins and vascular smooth muscle. All studies cited were published prior to 1992. CONCLUSIONS: Transplant atherosclerosis appears to result from a 'response to injury' of the endothelium, similar to naturally occurring atherosclerosis. The injury is diffuse, chronic and related to immune and nonimmune factors. Cellular and antibody-mediated rejection, cytomegalovirus infection and cytokine-induced vessel wall cell proliferation provide potential targets for future pharmacological and biological therapy.

Leiomyosarcoma of the left atrium: case report and review of the literature.

Leiomyosarcomas are extremely rare primary cardiac tumours. A 46-year-old woman presenting with symptoms and signs of rapidly progressive left ventricular failure and apparent systemic lupus erythematosus was subsequently found to have a grade III/III left atrial leiomyosarcoma which was confirmed surgically. Pathology showed a cellular neoplasm arranged in fascicles with multinucleated giant cells, with areas of high grade sarcomatous change. The patient died seven months postoperatively with intractable heart failure. At autopsy, tumour infiltrated the pericardium, both atria and the right ventricle, with invasion of the diaphragm and posterior mediastinum. The current world literature is reviewed with respect to this rare and often misdiagnosed tumour.