Myeloid PFKFB3 in atherosclerosis

Atherosclerosis is a chronic inflammatory disease of arterial vessel wall, and glycolysis is enhanced in macrophage-rich atherosclerotic arteries. 6-phosphofructo-2-kinase/fructose-2, 6-bisphophatase isoform 3 (PFKFB3) is a critical enzyme for regulation of glycolysis in vascular cells and leukocytes. It catalyzes the synthesis of fructose-2,6-bisphophate (F2, 6P2), and F2, 6P2 is the most potent allosteric activator of 6-phosphofructo-1-kinase (PFK-1). The latter is one of three rate-limiting enzymes for glycolysis. Activated monocytes/macrophages, dendritic cells and T cells predominantly use glycolysis to generate ATP, and these cells have high levels of PFKFB3. Glycolytic inhibition is efficacious in the treatment of many inflammatory diseases in animal models. However, the effect of PFKFB3 in myeloid cells on atherosclerosis has not been tested. In this project, we generated PFKFB3-floxed mice and mice with PFKFB3 deficiency in myeloid cells. Using these mice, we will investigate whether and how PFKFB3 deficiency in monocytes/macrophages affect atherosclerosis. To fulfil this objective, three specific aims will be pursued. Specific aim 1 is to investigate whether and how monocyte PFKFB3 deficiency affects monocyte recruitment to atherosclerotic arteries. Specific aim 2 is to investigate whether and how myeloid cell PFKFB3 deficiency affects monocyte/macrophage proliferation, activation and foam cell formation. Specific aim 3 is to study the role of myeloid PFKFB3 deficiency in the formation of atherosclerotic lesions in mice. The successful completion of our objectives is expected to bring about significant changes in the concepts and treatment/prevention methods that currently are well characterized in the field of atherosclerosis. (AHA Program: Grant-in-Aid)