Abstract Vascular complications in elderly people with diabetes continue to be major health problems throughout the world, yet lipid-associated mechanism for disrupting vascular integrity is unclear. As a major type of covalent lipid modifications, reversible protein S-palmitoylation has emerged as a potentially critical post-translational process in signaling pathway. Our studies suggest that the protein depalmitoylation enzyme APT1 is critical for ischemic vascular remodeling that is relevant to peripheral artery disease. By integrating in vitro studies, mouse models and patient specimen analysis, the research plan will lead to the identification and characterization of APT1-dependent R-Ras palmitoylation dynamics in vascular complications of diabetic patients. The result of the study will warrant the future focus on the role of lipid modification in pathophysiology and offer the promise of discovering novel targets for peripheral artery disease in elderly patient with diabetes.