Many recent reports provide strong evidence that MCP- 1 plays a major role in the development of ischemic heart disease (IHD) that is responsible for the majority of the 5 million human heart failure cases in the US, but the underlying mechanism is not known. We postulate that MCP-1-induced gene expression changes in the monocytes and the consequent production of cytokines and other biologically active molecules, as well as possible direct effects of MCP- 1 on the major cell types in the myocardium can lead to the development of IHD. IHD probably develops as a net consequence of the interplay of these events which involve many cell types and many biologically active molecules. Therefore in vitro studies on isolated cells cannot accurately reflect the interactions involved in IND. On the other hand a genomic approach can discover the genes whose altered expression in the heart leads to the development of IHD. Such an approach, although not possible on humans, can be done on a suitable animal model. We have developed a transgenic murine model that faithfully recapitulates most features of human IRD. Use of this model has a high likelihood of discovering novel genes as illustrated by our discovery of a previously unknown MCP-1-induced protein (MCPIP). With this overall objective we propose to pursue the following specific aims: 1.) Identify gene expression changes that occur in the ventricle during IHD development induced by targeted expression of MCP 1 in the CMC of transgenic mice using gene chip technology. 2.) Determine the function of the novel MCPIP: a) Determine whether a) MCPIP expression causes cell death, b) this death is enhanced by MCP-l and its receptor CCR2, c) whether the cell death shares features characteristic of apoptosis, d) MCPIP has a transcription factor-like activity and whether structural features required for this activity are also required for the cell death-inducing activity. 3.) Assess the role of apoptosis in the development of MCP 1-induced cardiovascular disease by testing whether a) prevention of monocyte apoptosis by targeted expression of Bc12 or b) prevention of apoptosis by absence of Fas or expression of sFas in the myocytes would delay or rescue the development of the disease. The approach proposed here will identify MCP-l induced alterations in the expression of known genes not previously implicated in IHD and novel genes of unknown function that are involved in IHD. These genes are likely to reveal novel targets for intervention in IND and genes with prognostic value.
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