This multidisciplinary renewal probes mechanism in atherogenesis, emphasizing those cells implicated in pathogenesis, namely EC, SMC, and the mononuclear phagocyte (MP). After major revisions, including the deletion of one project, and the complete restructuring of another, the more focused PROGRAM PROJECT comprises 4 complementary projects and 4 core units. PROJECT A employs a parallel plate channel flow viscometric device to explore biologic responses of vascular EC to steady state and oscillatory laminar shear stress, emphasizing changes in cell stiffness, intracellular potential and LDL and Ac-LDL receptor expression and function. Mechanisms of hemodynamic signal transduction are examined with emphasis on EC membrane fluidity (DPH), phosphoinositide turnover, Ca++ mobilization (Fura 2), and cytoskeletal function. In PROJECT B, a major thrust is the expression of the MP Acetyl-LDL receptor with emphasis on the regulatory role of MP activation and differentiation. This project will isolate, purify, and characterize the Ac-LDL receptor of rabbit granuloma macrophages, including its complete primary amino acid sequence. Studies will examine the relative contributions of receptor and non-receptor mediated pathways (pino-phagocytosis) for Lp uptake and metabolism (LDL, Ac-LDL, beta-VLDL) by granuloma macrophages from normal and WHHL rabbits, and the influence of induced activation (gamma-IFN, LPS) on MP Lp receptor expression and function. PROJECT C, focuses on the biology of MP recruitment to the arterial intima. A major emphasis is to determine the structural and functional homology of the 12Kd monocyte chemoattractant (SMC-CF) secreted by arterial SMC and the chemoattractant isolated from lesion-prone areas of the pig aorta (SACF). Studies will compare these two chemoattractants immunochemically, and in terms of receptor expression, and will characterize the biologic functions of SMC-CF both in vitro and in vivo. In vivo studies utilize two established models, namely the Alzet osmotic pump to deliver SMC-CF to the pig aorta, and the Florey rabbit ear chamber. PROJECT D employs glycoprotein processing inhibitors to probe the roles of N linked oligosaccharides in cultured SMC and normal, internalization- defective and receptor-negative FH fibroblasts on LDL receptor synthesis, processing, recycling and LDL metabolism in terms of lysosomal targeting and activities. All 4 projects depend upon CORE units in cell culture, biochemistry, pathology and administration. Quality is monitored by internal and external advisory committees.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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University of Texas Health Science Center San Antonio
Schools of Medicine
San Antonio
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Helmlinger, G; Berk, B C; Nerem, R M (1996) Pulsatile and steady flow-induced calcium oscillations in single cultured endothelial cells. J Vasc Res 33:360-9
Thoumine, O; Nerem, R M; Girard, P R (1995) Changes in organization and composition of the extracellular matrix underlying cultured endothelial cells exposed to laminar steady shear stress. Lab Invest 73:565-76
Marra, F; Grandaliano, G; Valente, A J et al. (1995) Thrombin stimulates proliferation of liver fat-storing cells and expression of monocyte chemotactic protein-1: potential role in liver injury. Hepatology 22:780-7
Wenzel, U O; Fouqueray, B; Grandaliano, G et al. (1995) Thrombin regulates expression of monocyte chemoattractant protein-1 in vascular smooth muscle cells. Circ Res 77:503-9
Helmlinger, G; Berk, B C; Nerem, R M (1995) Calcium responses of endothelial cell monolayers subjected to pulsatile and steady laminar flow differ. Am J Physiol 269:C367-75
Thoumine, O; Nerem, R M; Girard, P R (1995) Oscillatory shear stress and hydrostatic pressure modulate cell-matrix attachment proteins in cultured endothelial cells. In Vitro Cell Dev Biol Anim 31:45-54
Schwartz, C J; Valente, A J; Hildebrandt, E F (1994) Prevention of atherosclerosis and end-organ damage: a basis for antihypertensive interventional strategies. J Hypertens Suppl 12:S3-11
Grandaliano, G; Valente, A J; Abboud, H E (1994) A novel biologic activity of thrombin: stimulation of monocyte chemotactic protein production. J Exp Med 179:1737-41
Zhu, J F; Valente, A J; Lorenzo, J A et al. (1994) Expression of monocyte chemoattractant protein 1 in human osteoblastic cells stimulated by proinflammatory mediators. J Bone Miner Res 9:1123-30
Grandaliano, G; Valente, A J; Rozek, M M et al. (1994) Gamma interferon stimulates monocyte chemotactic protein (MCP-1) in human mesangial cells. J Lab Clin Med 123:282-9

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