Dietary obesity, insulin resistance (IR) and type-2 diabetes mellitus (T2DM) are the major risk factors for the development of cardiovascular diseases (CVDs). Recent studies have shown that reactive oxygen species (ROS)-generating enzyme, NADPH oxidase (Nox), causes endothelial oxidative stress and is a prominent feature underlying vascular abnormalities of patients with IR and T2DM. The Nox2 has been found to be constitutively expressed in endothelial cells (ECs) and can be activated in diabetic condition. It is known that short chain fatty acids (SCFAs) i.e. acetate (NaA), propionate (NaP) and butyrate (NaB) are byproducts of bacterial fermentation of resistant starch in the colon and exert beneficial effects in improving insulin sensitivity, colonic cancer and reducing CVDs development. However, the effects of SCFAs in reducing endothelial oxidative stress and dysfunction are still unknown. In this project, I have investigated high glucose (0-30 mM for 24 h)-induced ROS production, Nox2 activation levels, endothelial function (in terms of cell cycle regulation and capillary formation on matrigels), G protein-coupled receptor 43 levels (GPCR43, a SCFAs receptor) and the potential therapeutic effect of SCFAs in diabetes using cultured human pulmonary microvascular ECs (HPMEC). My results have shown that high glucose (30 mM) induced endothelial Nox2 activation and ROS production, which causes ECs cycle deregulation, cell apoptosis and capillaries broken down on matrigels. High glucose increases the levels of cyclin D, E, A and B, p53 and p16 protein expression which lead to abnormal ECs cell cycle regulation, apoptosis and cell death. Adding NaA (5 mM, GPCR43 agonist) into the culture medium can increase the GPCR43 expression on ECs under high glucose conditions, inhibits Nox2-induced ROS production and activation as well as improves ECs function. In short, high glucose causes endothelial oxidative stress and dysfunction via Nox2-induced ROS production. NaA activated GPCR43 inhibits Nox2 activation which reversed high glucose-induced damage on the ECs. SCFAs such as NaA may have the therapeutic potential for treating oxidative stress-related vascular complications in patients with IR, obesity and diabetes.