Both type 1 diabetes mellitus (T1DM) and T2DM increase the risk of atherosclerosis, the leading cause of death in diabetic patients. During the current funding period, we showed that the enzyme acyl-CoA synthetase 1 (ACSL1) is a critical mediator of myeloid cell activation and atherosclerosis in diabetic mice and that ACSL1 is upregulated in myeloid cells in humans with T1DM. We now wish to focus on two key unresolved issues:
Aim 1 : What are the critical intracellular mediators and downstream effects of the ACSL1- dependent pathway that activates myeloid cells in diabetes? We hypothesize that a distinct arm of toll-like receptor 4 (TLR4) signaling involving the adapter proteins TRAF and TRIF acts upstream of ACSL1 to activate monocytes and macrophages and that inflammatory activation mediated by ACSL1 is due to increased prostaglandin E2 (PGE2) production and activation of the PGE2 receptor EP4, promoting increased cytokine production and increased macrophage accumulation in atherosclerotic lesions. We will analyze myeloid ACSL1 induction and atherosclerosis in non-diabetic and diabetic LDL receptor-deficient (Ldlr-/-) mice with and without TRIF- and EP4-deletions targeted to myeloid cells. We will explore the downstream effects of ACSL1 by overexpressing ACSL1 under control of the myeloid cell-specific CD68 promoter. Studies on downstream effects of ACSL1 induction will include monocyte adhesion/migration and eicosanoid production. Furthermore, by overexpressing ACSL1 in myeloid-targeted EP4-deficient mice, we will gain understanding of to what extent the effects of ACSL1 are mediated through EP4 activation. We will complement our mouse studies by investigating activation of the ACSL1 pathway in human monocytes from control subjects and T1DM and T2DM patients.
Aim 2 : Do hyperglycemia and dysfunctional HDL promote the ACSL1-dependent pathway and atherosclerosis in diabetes? We hypothesize that hyperglycemia, by promoting TLR4-TRIF activation, induces ACSL1 expression in diabetic mice and that diabetic HDL contributes to ACSL1 induction and atherosclerosis by failing to suppress activation of the TLR4-TRIF pathway. This hypothesis will be tested by lowering blood glucose in diabetic mice, using an inhibitor of sodium-glucose linked transporter 2. We will also test the proposal that diabetes induces HDL dysfunction by altering the lipoprotein's ability to inhibit the TLR4- TRIF-ACSL1 pathway in myeloid cells, whether the ACSL1 pathway is required for the loss of anti- inflammatory effects of diabetic HDL, and the effect of HDL dysfunction on atherosclerosis. Collectively, the proposed studies should identify key steps in myeloid activation that result from induction of ACSL1 and that are of crucial importance in diabetes-accelerated atherosclerosis.
These studies will elucidate the mechanisms involved in diabetes-accelerated atherosclerosis and cardiovascular disease. Identification of such mechanisms might help develop treatment strategies to target cardiovascular disease in diabetic patients.
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