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The macrophage in human and experimental atherosclerosis
330
Thursday 13 October 1994: Workshop Abstracts W15 THE MONOCYTE-MACROPHAGE The monocyte-macrophage; introduction and overview &&&&J, Valente AL Dept. Pathol., Graduate Sch. of Biomed. Sci.. Univ. of Texas Health Sciences Center, 7703 Floyd Curl Drive, San Antonio, TX 78284-7750, USA
With the evolution of the concept of atherosclerosis as an inflammatory disorder, considerable interest has focused on monocyte recruitment to the arterial intima, including the roles of chemoattractants such as monocyte chemotactic protein-l (MCP-I), and a spectrum of endothelial leukocyte adhesion molecules @LAMS). The potential impacts of the macrophage on atherogenesis am pleiotropic, and include expression of the scavenger receptor pathway(s) for modified lipoproteins, free radical generation, and an array of secretory products including (i) hydrolases such as collagenase, elastase, and heparan sulfate endoglycosidase; (ii) bioactive lipids such as platelet activating factor(s), thromboxane B2, prostaglandin E2, and the leukotrienes (B4, C4); (iii) cytokines and other proteins including apolipoprotein E, a2macroglobuiin, colony stimulating factors, interleukin-1 and -6, tumor necrosis factor, platelet-derived growth factors, transforming growth factor-b and fibroblast growth factor(s); (iv) components of complement; and (v) coagulation and hemostatic agents, including Factors II, VII, IX, X and XIII, thromboplastin, and plasminogen activators (t-PA, u -PA). The biologic and pathogenic significance of such diverse roles are briefly discussed in the light of our evolving understanding of the nature of atherogenesis. The macrophage in human and experimental atherosclerosis f&~&& Antonov AS, Bell FP, Virmani R, Kolodgie FD, Dept. of Paihol., Med. Coil. of Georgia, Augusta, GA 30912, USA
Recruitment of monocytes into the arterial wall and their transition into macrophage (M#) foam cells is considered to be an early and important cellular event in atherogenesis. However, little is known concerning either the functional state of monocytes prior to their recruitment and transition into foam cells in an atherogenie environment, or functional alterations induced during tecruitment. This study compares blood monocyte and M$J foam cell lipid content and synthesis in hyperlipemic (HL) and normolipemic (NL) swine and examines monocyte proliferation induced by coculture with aortic endothelium. Blood monocytes from I-IL swine show higher total lipid, cholesterol, phospholipid, and cholesteryl ester (2, 3, 2 and 14 fold, respectively) than in NL swine. They also demonstrate a 65% increase in ACAT activity and signiticand elevated (2-4 fold for various lipid classes) lipid synthesis from T4C-acetate and oleate; even greater (range 3-70 fold) differences are seen in isolated early lesions rich in M@ foam cells (>90% of cell content). Monocytes isolated from either swine or human blood and cocultured on homologous endothehum show thymidine indices as high at 508, resulting in 6-10 fold increases in M# number between 4 and 8 days in coculture. The induced proliferation is contact-dependent. Monocytes cultured alone show ~2% thymidine index. We hypothesize that circulating monocytes in HL conditions are metabolically preconditioned for more effective function prior to their entry into the intima. Their enhanced lipid synthesis capabilities facilitate their transition into M$ foam cells by converting highly mobile lipoprotein/lipid hydrolysis products into storable lipids. Moreover, contact with the endothelium during recruitment into the intima may induce monocyte proliferation, resulting in increased numbers of lesion M#.
IN ATHEROGENESIS
Adhesion molecules in intimal monocyte-macrophage recruitment wp, Dept. of Med., Bn@am and Women’s Hosp. and Harvard Med. Sch., 221 Longwood Avenue, Boston, MA 02115, USA
Monocyte adhesion to surface of endothelial cells and penetration into the intima occur early in atherogenesis. In the latter stages of lesion development, neovascular plexi provide a large surface ama for potential monocyte recruitment. Endothelial cells (EC) can express inducibly a number of adhesion molecules on their surface that bind various classes of leukocytes. In particular, vascular cell adhesion molecule-l (VCAM-1) exhibits selectivity for monocytes and lymphocytes, precisely the types of leukocytes that accumulate within developing atheroma. Endothelium in lesion-prone amas of the rabbit aorta express VCAM-1 as early as 1 week after initiating a hypercholesterolemic diet, before intimal macrophages accumulate. Other adhesion molecules may also contribute to this process, including intercellular adhesion molecule-l (ICAM-1) and perhaps others yet to be fully characterized. Once attached to the EC chemoattractant, stimuli such as monocyte chemoattractant protein-l (MCP-1) may promote their transendothelial migration. Vascular EC, smooth muscle cells (SMC), and leukocytes can express MCP-1 inducibly, and human and experimental atherosclerotic lesions exhibit increased expression of this chemokine. Once within the expanding intima, monocytes can evolve into foam cells that can elaborate numerous mediators that may contribute to lesion evolution and complication, including modulators of SMC proliferation, lipid metabolism, various cytokines, and factors that alter the metabolism of the extracellular matrix. Atherosclerotic plaques produce macrophage-colony stimulating factor (M-CSF), a potential activator of many of these macrophage functions. Thus, the recruitment and actions of mononuclear phagocytes may contribute decisively to initiation, evolution, and complication of the atherosclerotic plaque. Monocyte-macrophage recruitment to the arterial intima: a role for MCP-1 and its receptor Dept. of Pathol., Graduate Sch. of Biomed. Sci., m, Univ. of Texas Health Sciences Center, 7703 Floyd Curl Drive, San Antonio, TX 78284-7750, USA
Monocyte recruitment to the intima is a process which most probably occurs throughout all stages of plaque pathogenesis. One mechanism involved in leukocyte accumulation in the tissue is the generation of specific chemoattractants and mediators of leukocyte activation at the site of inflammation. In recent years numerous monocyte chemoattractants of potential importance in the pathogenesis of atherosclerosis have been identified, including thrombin, degradation products of matrix protein, oxidized LDL and members of the -C-C- subclass of the chemokine family of genes (e.g. MCP-l/JE, RANTES, MIP). MCP-1 is the product of an early response gene (MCP-l/IE) expressed in a wide variety of tissue types. It is induced by cytokines and other stimuli including IL-l, IL-6. TNF, GM-CSF, MCSF, IFN-y, IFN-a, endotoxin, modified LDL and thrombin. In chemotactic assays using freshly isolated peripheral blood leukocytes, MCP-1 appears to be monocyte-specific. This is supported by binding data with labeled MCP-1, which identified highafftnity receptor binding sites on freshly isolated monocytes but not on lymphocytes or polymorphonuclear leukocytes. Recent studies indicate that the receptors for the chemokines belong to the 7-transmembrane-domain receptor family with G-protein
Atherosclerosis X, Montreal, October 1994
Thursday 13 October 1994: Workshop Abstracts W15 THE MONOCYTE-MACROPHAGE The monocyte-macrophage; introduction and overview &&&&J, Valente AL Dept. Pathol., Graduate Sch. of Biomed. Sci.. Univ. of Texas Health Sciences Center, 7703 Floyd Curl Drive, San Antonio, TX 78284-7750, USA
With the evolution of the concept of atherosclerosis as an inflammatory disorder, considerable interest has focused on monocyte recruitment to the arterial intima, including the roles of chemoattractants such as monocyte chemotactic protein-l (MCP-I), and a spectrum of endothelial leukocyte adhesion molecules @LAMS). The potential impacts of the macrophage on atherogenesis am pleiotropic, and include expression of the scavenger receptor pathway(s) for modified lipoproteins, free radical generation, and an array of secretory products including (i) hydrolases such as collagenase, elastase, and heparan sulfate endoglycosidase; (ii) bioactive lipids such as platelet activating factor(s), thromboxane B2, prostaglandin E2, and the leukotrienes (B4, C4); (iii) cytokines and other proteins including apolipoprotein E, a2macroglobuiin, colony stimulating factors, interleukin-1 and -6, tumor necrosis factor, platelet-derived growth factors, transforming growth factor-b and fibroblast growth factor(s); (iv) components of complement; and (v) coagulation and hemostatic agents, including Factors II, VII, IX, X and XIII, thromboplastin, and plasminogen activators (t-PA, u -PA). The biologic and pathogenic significance of such diverse roles are briefly discussed in the light of our evolving understanding of the nature of atherogenesis. The macrophage in human and experimental atherosclerosis f&~&& Antonov AS, Bell FP, Virmani R, Kolodgie FD, Dept. of Paihol., Med. Coil. of Georgia, Augusta, GA 30912, USA
Recruitment of monocytes into the arterial wall and their transition into macrophage (M#) foam cells is considered to be an early and important cellular event in atherogenesis. However, little is known concerning either the functional state of monocytes prior to their recruitment and transition into foam cells in an atherogenie environment, or functional alterations induced during tecruitment. This study compares blood monocyte and M$J foam cell lipid content and synthesis in hyperlipemic (HL) and normolipemic (NL) swine and examines monocyte proliferation induced by coculture with aortic endothelium. Blood monocytes from I-IL swine show higher total lipid, cholesterol, phospholipid, and cholesteryl ester (2, 3, 2 and 14 fold, respectively) than in NL swine. They also demonstrate a 65% increase in ACAT activity and signiticand elevated (2-4 fold for various lipid classes) lipid synthesis from T4C-acetate and oleate; even greater (range 3-70 fold) differences are seen in isolated early lesions rich in M@ foam cells (>90% of cell content). Monocytes isolated from either swine or human blood and cocultured on homologous endothehum show thymidine indices as high at 508, resulting in 6-10 fold increases in M# number between 4 and 8 days in coculture. The induced proliferation is contact-dependent. Monocytes cultured alone show ~2% thymidine index. We hypothesize that circulating monocytes in HL conditions are metabolically preconditioned for more effective function prior to their entry into the intima. Their enhanced lipid synthesis capabilities facilitate their transition into M$ foam cells by converting highly mobile lipoprotein/lipid hydrolysis products into storable lipids. Moreover, contact with the endothelium during recruitment into the intima may induce monocyte proliferation, resulting in increased numbers of lesion M#.
IN ATHEROGENESIS
Adhesion molecules in intimal monocyte-macrophage recruitment wp, Dept. of Med., Bn@am and Women’s Hosp. and Harvard Med. Sch., 221 Longwood Avenue, Boston, MA 02115, USA
Monocyte adhesion to surface of endothelial cells and penetration into the intima occur early in atherogenesis. In the latter stages of lesion development, neovascular plexi provide a large surface ama for potential monocyte recruitment. Endothelial cells (EC) can express inducibly a number of adhesion molecules on their surface that bind various classes of leukocytes. In particular, vascular cell adhesion molecule-l (VCAM-1) exhibits selectivity for monocytes and lymphocytes, precisely the types of leukocytes that accumulate within developing atheroma. Endothelium in lesion-prone amas of the rabbit aorta express VCAM-1 as early as 1 week after initiating a hypercholesterolemic diet, before intimal macrophages accumulate. Other adhesion molecules may also contribute to this process, including intercellular adhesion molecule-l (ICAM-1) and perhaps others yet to be fully characterized. Once attached to the EC chemoattractant, stimuli such as monocyte chemoattractant protein-l (MCP-1) may promote their transendothelial migration. Vascular EC, smooth muscle cells (SMC), and leukocytes can express MCP-1 inducibly, and human and experimental atherosclerotic lesions exhibit increased expression of this chemokine. Once within the expanding intima, monocytes can evolve into foam cells that can elaborate numerous mediators that may contribute to lesion evolution and complication, including modulators of SMC proliferation, lipid metabolism, various cytokines, and factors that alter the metabolism of the extracellular matrix. Atherosclerotic plaques produce macrophage-colony stimulating factor (M-CSF), a potential activator of many of these macrophage functions. Thus, the recruitment and actions of mononuclear phagocytes may contribute decisively to initiation, evolution, and complication of the atherosclerotic plaque. Monocyte-macrophage recruitment to the arterial intima: a role for MCP-1 and its receptor Dept. of Pathol., Graduate Sch. of Biomed. Sci., m, Univ. of Texas Health Sciences Center, 7703 Floyd Curl Drive, San Antonio, TX 78284-7750, USA
Monocyte recruitment to the intima is a process which most probably occurs throughout all stages of plaque pathogenesis. One mechanism involved in leukocyte accumulation in the tissue is the generation of specific chemoattractants and mediators of leukocyte activation at the site of inflammation. In recent years numerous monocyte chemoattractants of potential importance in the pathogenesis of atherosclerosis have been identified, including thrombin, degradation products of matrix protein, oxidized LDL and members of the -C-C- subclass of the chemokine family of genes (e.g. MCP-l/JE, RANTES, MIP). MCP-1 is the product of an early response gene (MCP-l/IE) expressed in a wide variety of tissue types. It is induced by cytokines and other stimuli including IL-l, IL-6. TNF, GM-CSF, MCSF, IFN-y, IFN-a, endotoxin, modified LDL and thrombin. In chemotactic assays using freshly isolated peripheral blood leukocytes, MCP-1 appears to be monocyte-specific. This is supported by binding data with labeled MCP-1, which identified highafftnity receptor binding sites on freshly isolated monocytes but not on lymphocytes or polymorphonuclear leukocytes. Recent studies indicate that the receptors for the chemokines belong to the 7-transmembrane-domain receptor family with G-protein
Atherosclerosis X, Montreal, October 1994