Atherosclerosis is a chronic inflammatory disease and remains one of the major causes of death globally, despite aggressive risk stratifications including smoking cessation, optimal control of lipid, blood pressure, and diabetes. Antioxidant therapies with vitamin E and C or β-carotene failed to achieve significant clinical benefits in patients with cardiovascular diseases (CVD) including atherosclerosis. New therapies including interleukin-1β monoclonal antibody canakinumab and anti-inflammatory drug colchicine could significantly reduce the rate of major adverse cardiovascular events (MACE) including nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. However, canakinumab therapy did not decrease all-cause mortality, and was associated with a significant increase in the incidence of fatal infection (including sepsis), and high cost. While colchicine is a generic drug and decreases the rate of MACE, colchicine therapy is associated with a significant increase in death from non-cardiovascular causes5. Thus, alternative options are needed to attenuate atherosclerosis. N-acetylcysteine (NAC) has been traditionally considered an antioxidant although it is more like an anti-inflammatory agent, and could effectively attenuate reactive oxygen species (ROS) production, and reduce vascular inflammation. NAC significantly decreases the progression of atherosclerosis in young apolipoprotein E-deficient mice and low-density lipoprotein receptor deficient (LDLR-/-) mice with an atherogenic high fat diet (HFD). NAC treatment delays cellular senescence in endothelial cells from atherosclerotic patients, and improves coronary and peripheral endothelium-dependent vasodilation in human subjects with or without atherosclerosis. NAC treatment also inhibits oxidized LDL-induced foam cell formation and suppresses matrix-degrading capacity of foam cells. However, it is unclear if NAC could attenuate the progression of atherosclerosis or reverse the course of atherosclerosis in aging mice. Diabetes mellitus (DM) significantly increases the risk of developing severe peripheral artery disease (PAD) with critical limb ischemia (CLI) and chronic ulcers. Due to poor healing, patients with diabetic CLI may need limb amputation that accounts for about 60% of all non-traumatic amputations in the U. S. After a two decade reduction in diabetes-related non-traumatic lower-extremity amputation, recent data show an increase in amputation, particularly in young and middle-aged adults. In addition, major randomized clinical trials have shown that blood glucose-lowering or anti-hypertensive therapies have very limited effects on reducing macrovascular complications, and no benefit on amputation rates in diabetic patients. These highlight an urgent need for alterative effective approaches to promoting the recovery of diabetic ischemic limb to reduce lower-extremity amputation in DM. It is known that reactive oxygen species (ROS) production and oxidative stress are significantly increased in DM, and excessive oxidative stress is closely involved in the development of diabetic complications, including cardiovascular diseases, nephropathy, and retinopathy. Although low levels of ROS function as signaling molecules to mediate various biological responses such as gene expression, cell proliferation, migration, angiogenesis, apoptosis, and senescence in endothelial cells (ECs), high levels of ROS could contribute to a variety of pathologic conditions, including reduced nitric oxide (NO) bioavailability, impairment of vascular function and other endothelial phenotypic abnormalities. The metabolic abnormalities in DM could cause mitochondrial superoxide overproduction in endothelial cells of both large and small vessels, as well as in the myocardium. Increased glucose levels could stimulate ROS production, leading to further glucose uptake and triggering cell toxicity and death. In addition, increased formation of advanced glycation end-products (AGEs) could enhance the activity of ROS-generating enzymes including NADPH oxidase, exacerbating oxidative stress and mitochondrial superoxide production. Thus, the objectives of the proposed study are: 1) to investigate the effect of NAC treatment on the outcomes in patients with advanced atherosclerotic heart diseases and not a candidate for revascularization; and 2) to investigate the effect of NAC treatment on the outcomes in diabetic patients with significant peripheral artery disease.