The onset of atherosclerosis is marked by the migration of medial smooth muscle cells into the intima where these cells proliferate and produce abundant, extracellular fibers of collagen and elastin. The resulting accumulation of matrix, coupled with its ability to bind extracellular lipid, is a major source of the increasing mass of the atherosclerotic lesion. The overall goal of this project is to determine the mechanisms and regulation of arterial matrix accumulation and degradation with particular regard to the influence of atherogenic factors of both environmental and cellular origin, thus contributing knowledge essential to the eventual control of this major human disease. Toward these ends, we will employ aortic smooth muscle cell cultures which have been developed by our program as models of the normal and diseased arterial wall. These culture systems, derived from neonatal rat and rabbit aorta, respectively, exhibit structural features, matrices and metabolic responses which emulate those of the arterial wall. Thus, the opportunity is provided to control the extent of perturbant or injury exposure and to characterize intra- and extracellular regulatory responses relatively free of the analytical complexities of arterial tissue. The staff of this project includes both senior and junior faculty and supporting staff members, constituting a team of investigators with considerable expertise in the theoretical and experimental aspects of the biochemistry, molecular and cell biology, and enzymology of the extracellular matrix. The areas of expertise of the individual project leaders complement each other well, and their research efforts will be highly integrated to provide in depth analyses of the biosynthetic and degradative responses of the cell culture models to atherogenic injuries and perturbations. Project 27 is concerned with the development of cell culture models of proteolytic and lipid-induced arterial injury and with the definition of levels of regulation of collagen, elastin and lipoprotein in these models. Project 34 will investigate the regulation of specific genetic types of collagen assessing for transcriptional control mechanisms including regulatory elements and factors mediating expression, as these are influenced by atherogenic stimuli. Project 28 will be concerned with the regulation and biosynthetic processing of lysyl oxidase in these culture systems. Lysyl oxidase catalytically initiates crosslinking of elastin and collagen into insoluble fibers and thus can control the development of fibrotic lesions. Project 36 focuses on mechanisms whereby insulin-like growth factor-I differentially regulates smooth muscle cell elastogenesis as a function of age, hormone concentration, and cell type. These projects are supported by two core units providing cell cultures, molecular and immunological probes, microscopy and administrative support essential to this project.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Boston University
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Lucero, Héctor A; Mäki, Joni M; Kagan, Herbert M (2011) Activation of cellular chemotactic responses to chemokines coupled with oxidation of plasma membrane proteins by lysyl oxidase. J Neural Transm (Vienna) 118:1091-9
Chen, Hongjie; Koupenova, Milka; Yang, Dan et al. (2011) Regulation of MMP-9 expression by the A2b adenosine receptor and its dependency on TNF-? signaling. Exp Hematol 39:525-30
Yang, D; Chen, H; Koupenova, M et al. (2010) A new role for the A2b adenosine receptor in regulating platelet function. J Thromb Haemost 8:817-27
Grimsby, Jessica L; Lucero, Hector A; Trackman, Philip C et al. (2010) Role of lysyl oxidase propeptide in secretion and enzyme activity. J Cell Biochem 111:1231-43
St Hilaire, Cynthia; Carroll, Shannon H; Chen, Hongjie et al. (2009) Mechanisms of induction of adenosine receptor genes and its functional significance. J Cell Physiol 218:35-44
Wu, Xiaoyan; Kong, Xiaocen; Luchsinger, Larry et al. (2009) Regulating the activity of class II transactivator by posttranslational modifications: exploring the possibilities. Mol Cell Biol 29:5639-44
Chen, Hongjie; Yang, Dan; Carroll, Shannon H et al. (2009) Activation of the macrophage A2b adenosine receptor regulates tumor necrosis factor-alpha levels following vascular injury. Exp Hematol 37:533-8
Chandrasekharan, Bindu P; Kolachala, Vasantha L; Dalmasso, Guillaume et al. (2009) Adenosine 2B receptors (A(2B)AR) on enteric neurons regulate murine distal colonic motility. FASEB J 23:2727-34
St Hilaire, Cynthia; Koupenova, Milka; Carroll, Shannon H et al. (2008) TNF-alpha upregulates the A2B adenosine receptor gene: The role of NAD(P)H oxidase 4. Biochem Biophys Res Commun 375:292-6
Lucero, Hector A; Ravid, Katya; Grimsby, Jessica L et al. (2008) Lysyl oxidase oxidizes cell membrane proteins and enhances the chemotactic response of vascular smooth muscle cells. J Biol Chem 283:24103-17

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