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.

Clarification of serotonin‐induced effects in peripheral artery disease observed through the femoral artery response in models of diabetes and vascular occlusion: The role of calcium ions

“…In the first part of this study, serotonin produced concentration‐dependent contraction of the isolated rat femoral artery in all groups and subgroups. This was expected because serotonin is well known as a compound that produces contractile effects in the arteries of different animal species . The serotonin‐induced contraction was endothelium‐dependent in the group of healthy animals, but it was independent of the endothelium presence in the rest of the groups/subgroups.…”

Obesity and Pulmonary Hypertension: A Review of Pathophysiologic Mechanisms

“…Obesity and its comorbidities are also associated with increased oxidative stress through lipid peroxidation, production of reactive oxygen species, and overexpression of xanthine oxidase [74]. Isolated pulmonary arteries of insulin resistant rats show diminished acetylcholine-mediated nitric oxide release, as well as upregulation of NADPH oxidase, 5-HT, and cycloxygenase-2 proteins [75–77]. Interestingly, in animal models, insulin resistance coupled with moderate hypoxia results in PH and right ventricular hypertrophy while neither insulin resistance nor hypoxemia alone induces PH or right ventricular hypertrophy [78].…”

Constrictor prostanoids and uridine adenosine tetraphosphate: vascular mediators and therapeutic targets in hypertension and diabetes

“…In diabetic animal models, COX‐2‐derived prostanoids have been suggested to induce abnormal vasoconstrictor responses or to account for the development of endothelium‐derived vasoconstrictor activity (Quilley and Chen, ; Bagi et al ., ; Guo et al ., ; Nacci et al ., ; Lopez‐Lopez et al ., ; Ramos‐Alves et al ., 2012a,b; Vessieres et al ., ). Indeed, COX‐2 expression and activity are increased in diabetic arteries (Bagi et al ., ; Sanchez et al ., ; Kassan et al ., ; Martinez et al ., ).…”