Submitted Abstract
ß3 integrins (ITGB3) occur as avß3 in various cell types and as aIIß3 exclusively in megakaryo/-thrombocytes. They play a role in many diseases, but antagonizing ITGB3 yielded mixed results in the treatment of malignant diseases or osteoporosis, and only short term intravenous, but not chronic oral antagonism of aIIß3 was beneficial in humans with coronary disease. Patients with a genetic defect in both the aIIbß3 and a¿ß3 integrins (Glanzmann thrombastenia) are not protected from atherosclerosis despite suffering from a severe bleeding disorder. Mice with a germline ITGB3 deficiency (ß3-/-) demonstrate that loss of ITGB3 gives very different results from its inhibition: ß3-/- mice show enhanced tumor growth and neoangiogenesis due to amplified angiogenic signaling in endothelial cells, but even myeloid-specific beta3 integrin deletion is sufficient to enhance growth of tumor xenografts. ß3-/- mice are also prone to systemic inflammation and atherosclerosis on high fat diet despite a severe bleeding predisposition. These observations suggest cell-autonomous roles of the ITGB3. We have demonstrated that bone marrow derived ITGB3 is strongly implicated in vivo and I hypothesize that ITGB3-dependent signaling in macrophages may be anti-inflammatory. In this proposal, the cell-specific roles of ITGB3 in cell types mostly relevant for the inflammatory atherogenic process will be investigated employing newly generated mice that highlight the ITGB3 expression in macrophages and Cre-Lox technology that allows tissue-specific deletion of the ITGB3. We will also attempt to amplify the expression of ITGB3 in macrophages to look if over-expression of ITGB3 would rescue mice from development of inflammation and atherosclerosis on high-fat diet.In addition, we will utilize high-throughput technologies to identify molecular pathways associated with ITGB3 with regards to inflammation and, atherogenesis in macrophages and smooth muscle cells. Knowledge about the cell-specific function of ITGB3 is important for proper risk-benefit assessment of a potential clinical use of non-selective ß3 integrin antagonists. It may also illuminate novel molecular pathways in (vascular) inflammation and cancer that may serve as alternative and/or better drug targets to treat chronic diseases.