A. Phillip Owens: My88 Deficiency, in Bone Marrow Derived Cells, Attenuates both AngII-Mediated Atherosclerosis and AAA

10. Project summary (must be completed on this page): Angiotensin II (Angll) infusion into hyperlipidemic mice enhances atherosclerosis and induces abdominal aortic aneurysms (AAAs). Although Angll promotes both vascular diseases, their pathologies imply they are generated via different mechanisms. A major difference is the intimal macrophage accumulation throughout the development of Angll-induced atherosclerosis, while macrophage accumulation in the media of the aorta is characteristic of the initial stages of Angll-induced AAA development. Macrophages are the most abundant cells in experimental atherosclerotic lesions. Osteopetrotic (op) mice, that lack M-CSF, have reduced circulating monocytes and markedly reduced atherosclerotic lesions in either apoE-/- or LDL receptor -/- backgrounds. Macrophages are present throughout the initiation and maturation stages of Angll-induced AAA formation, although their functional role has not been defined in this disease. Our lab has also used apoE deficient op mice to study the contribution of macrophages to AAA formation. However, the apoE -/- littermates, that were wild type for M-CSF, failed to develop a significant number of AAAs. This may have been attributable to the strain background of the op mice that differs from the C57BU6 background used for all other studies. Thus, the contribution of macrophages to AAA formation has not been determined. Recently, there has been considerable interest in myeloid differentiation factor 88 (MyD88) as a major regulator of innate immune signaling pathways. Consistent with this, MyD88 deficiency produces multiple defects in macrophage functions. Futhermore, MyD88 deficiency in apoE-/- mice decreases the size of atherosclerotic lesions. However, MyD88 is expressed in all cells involved in vascular pathology and the contribution of macrophage specific deficiency to lesion formation has not been determined. Hypothesis: MyD88 deficiency, in bone marrow derived cells, attenuates both Angll-mediated atherosclerosis and AAA via decreased macrophage accumulation in aortic tissue. Aim 1: Effects of MyD88 -/- will be determined in the pathogenesis of Angll induced atherosclerosis and AAA. Aim 2: The role of MyD88 in bone marrow-derived cells will be delineated in Angll-induced atherosclerosis and AAA.macrophage accumulation in aortic tissue. Aim 3: Determine the effects of MyD88 deficiency on the ability of macrophages to enter aortic tissue.