Inhalation Exposure to Cigarette Smoke Induces Endothelial Nitric Oxide Synthase Uncoupling and Enhances Vascular Collagen Deposition in Streptozotocin-Induced Diabetic Rats

Smoking is an acknowledged risk factor for vascular disorders, and vascular complication is a main outcome of diabetes. Hence, we investigated the impact of cigarette smoke on blood vessels in diabetes, postulating that smoking might aggravate diabetic vascular impairment. Sprague-Dawley rats were divided into four groups: control, cigarette smoke-exposed, diabetic, and cigarette smoke-exposed diabetic groups. Streptozotocin-induced diabetic rats were exposed to cigarette smoke by inhalation at total particulate matter concentration of 200 μg/L for 4 h/day, 5 day/week for a total of 4 weeks. Diabetes caused structural change of aorta, but additional cigarette smoke exposure did not induce further alteration. Collagen, a marker for fibrosis, was increased in media of diabetic aorta, and this increase was augmented by cigarette smoke. Cigarette smoke induced endothelial nitric oxide synthase (eNOS) uncoupling in the diabetic group. Malondialdehyde was increased and glutathione was decreased in blood from diabetes, but these effects were not exaggerated by cigarette smoke. Cigarette smoke caused NADPH oxidase (NOX) 2 expression in diabetic aorta and enhanced diabetes-induced NOX4 expression in aorta. Taken together, cigarette smoke exposure can aggravate vascular fibrosis and induce eNOS uncoupling in diabetes under experimental condition, suggesting that smoking might exacerbate diabetic vascular impairments.