THROMBOSPONDIN 1 MEDIATES MACROPHAGE INFILTRATION INTO ADIPOSE TISSUE AND PROMOT

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Obesity is becoming a global public health problem and is associated with an increased risk of cardiovascular diseases including atherosclerosis. Accumulating evidence suggests that obesity-induced chronic low-grade inflammation is an important mechanism for the adverse effects of adiposity on atherosclerosis. Thrombospondin1, a multifunctional extracellular matrix protein, has been shown to be up-regulated in adipose tissue of mice with diet or genetically induced obesity. Moreover, recent studies demonstrate that TSP1 expression is increased in adipocytes from obese humans and correlates positively to obesity and adipose tissue inflammation. Preliminary data demonstrate that adipose tissue from high fat (HF)-fed TSP1 deficient mice exhibits reduced numbers of infiltrating macrophages compared to HF-fed wild type controls. Importantly, reductions in macrophage infiltration into adipose tissue of TSP1-/- HF-fed mice were observed even though mice exhibited similar levels of obesity as wild type controls. In addition, TNF-alpha and IL-6 levels in adipose tissue and plasma were reduced in HF-fed TSP1-/- mice compared to controls. Expression of the cell adhesion molecule - ICAM was increased in aortic endothelial cells from HF-fed control, but not TSP1-/- mice, suggesting that TSP1 contributes to obesity-associated endothelial dysfunction. Moreover, incubation of cultured macrophages with TSP1 increased migration, while macrophages from TSP1-/- mice exhibited reduced macrophage migration. However, the specific domains of TSP1 responsible for macrophage infiltration, as well as the cell source of TSP1 contributing to obesity-induced macrophage infiltration are unknown. Importantly, effects of TSP1 deficiency on the development of atherosclerosis in the absence or presence of obesity have not been defined. The central hypothesis of this proposal is that specific domains of TSP1 mediate increased macrophage infiltration into adipose tissue with diet-induced obesity and promote atherosclerosis in apoE-/- mice. This hypothesis will be tested by determination of the specific domains of TSP1 responsible for increased macrophage adhesion and/or migration in aim 1. In aim 2, we will determine if TSP1 deficiency decreases atherosclerosis in apoE-/- mice with diet-induced obesity. These studies will provide novel information on the role of TSP1 in obesity associated atherosclerosis. Understanding the role of adipose tissue TSP1 in regulation of adipose tissue inflammation and its role in the development and progression of atherosclerosis in mice with diet-induced obesity will lead to development of therapeutic targets for treatment of this disease.