(Applicant's list of Aims) This proposal is based upon our new findings that the atherogenic lipoprotein Lp(a) induces vascular endothelial cells (ECs) to synthesize and secrete the CC chemokine, I-309, a monocyte and Th2 lymphocyte chemoattractant. The C-terminal domain of apo(a) is the portion of Lp(a) responsible. These findings define a new mechanism, distinct from oxidized lipids, by which a lipoprotein may induce a potent chemokine. This is the first documentation that I-309, a chemokine reported to be produced by monocytes/macrophages and T-lymphocytes, is an endothelial product. We hypothesize that the atherogenic effect of apo(a) is due in part to the induction of I-309 in ECs and that I-309 may play a major role in recruiting monocytes to the atherosclerotic plaque and the injured arterial wall. I-309 may thus be prothrombotic because activated monocytes and macrophages are a major source of tissue factor. This hypothesis is supported by our identification of I-309 in the human atherosclerotic plaque in the endothelium, in macrophages and in acellular areas. Apo(a) was found to extensively co-localize with I-309 in the plaque. In a mouse model of arterial injury, TCA-3, the mouse homologue of I-309, is located in the regenerated endothelium and in the neo-intimal layer containing vascular smooth muscle cells (VSMCs) and macrophages. Chemokine Receptor-8 (the I-309 receptor) mRNA was found in human umbilical vein endothelial cells (HUVECs). Our new data documents that I-309 is chemotactic for HUVECs suggesting that HUVEC CCR8 is functional. Thus I-309 may have autocrine effects on EC and may regulate both EC migration and vasculogenesis, suggesting that I-309 may represent a new target for the control of EC migration. We have identified I-309 antigen in platelets and in megakarocytes (Mks), and I-309 mRNA in human Mks by RT-PCR suggesting that Mks synthesize I-309. This represents a new activity for platelets. We propose that the release of I-309 by activated platelets may represent the initial chemotactic signal that attracts monocytes to sites of vascular injury. These observations form the basis for the present proposal.
Our specific aims are: 1. To establish the role of I-309 in endothelial migration and vasculogenesis. We will expand our observation that I-309 is chemotactic for HUVECs by establishing that I-309 is a chemoattractant for arterial and microvascular ECs. We will document that CCR8 is the specific functional receptor for I-309 on ECs. We will define the role of I-309 in EC invasion in an in vitro model, in the induction of EC metalloproteinases, and establish whether I-309 is vasculogenic in a mouse model of angiogenesis. We will determine whether the induction of I-309 is unique to apo(a) or is a property of other EC agonists as well. We will establish whether I-309 acts as an agonist for VSMCs. 2. To establish the role of I- 309 in platelets and megakaryocytes (Mks). We have found I-309 antigen in platelets and I-309 antigen and mRNA in megakaryocytes. We hypothesize that I-309 is released by activated platelets and may play an important role in early monocyte recruitment at sites of arterial injury. We will examine regulation of I-309 in Mks and determine whether platelet activation releases I-309. We will establish that platelet I-309 is chemotactic for monocytes and ECs. We will also determine whether platelet I-309 participates in leukocyte accumulation in several different dynamic models. 3. To study the role of TCA-3, the murine homologue of I-309, in mouse models of acute arterial injury. We hypothesize that TCA-3 acts to attract monocytes to the injured arterial wall and that functional absence of TCA-3 will result in decreased monocyte accumulation and intimal hyperplasia in a mouse model of femoral artery injury. We will examine the effect of neutralizing antibodies to mouse CCR8 and TCA-3 on the development of intimal hyperplasia in normal, in apoE-deficient, and in apoE/CCR2 double knockout mice. 4. To characterize the endothelial cell apo(a) receptor and to analyze signal transduction pathways stimulated by apo(a). Our data suggests that Ecs possess a receptor for apo(a). We propose to establish that the induction of I-309 by apo(a) is receptor-mediated and to characterize this receptor. We will initiate studies to analyze signal transduction pathways induced in HUVECs by apo(a).
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