Type 1 Diabetes-Induced Hyper-Responsiveness to 5-Hydroxytryptamine in Rat Pulmonary Arteries via Oxidative Stress and Induction of Cyclooxygenase-2

Abstract

Recent epidemiological data suggest that diabetes is a risk factor for pulmonary arterial hypertension. The aim of the present study was to analyze the link between type 1 diabetes and pulmonary arterial dysfunction in rats. Male Sprague-Dawley rats were randomly divided into a control group (saline) and a diabetic group (70 mg/kg streptozotocin). After 6 weeks, diabetic animals showed a down-regulation of the lung bone morphogenetic protein receptor type 2, up-regulation of 5-hydroxytryptamine (5-HT) 2A receptors and cyclooxygenase-2 (COX-2) proteins as measured by Western blot analysis, and increased contractile responses to 5-HT in isolated intrapulmonary arteries. The hyper-responsiveness to 5-HT was endothelium-independent and unaffected by inhibition of nitric-oxide synthase but prevented by indomethacin, the selective COX-2 inhibitor N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methane sulfonamide (NS-398), superoxide dismutase, and the NADPH oxidase inhibitor apocynin or chronic treatment with insulin. However, diabetic rats at 6 weeks did not develop elevated right ventricular pressure or pulmonary artery muscularization, whereas a longer exposure (4 months) to diabetes induced a modest, but significant, increase in right ventricular systolic pressure. In conclusion, type 1 diabetes mellitus in rats induces a number of changes in lung protein expression and pulmonary vascular reactivity characteristic of clinical and experimental pulmonary arterial hypertension but insufficient to elevate pulmonary pressure. Our results further strengthen the link between diabetes and pulmonary arterial hypertension.