Abstract
Reactive oxygen species (ROS) are involved in the pathologic process of pulmonary arterial hypertension as either mediators or inducers. Rutin is a type of flavonoid which exhibits significant scavenging properties on oxygen radicals both in vitro and in vivo. In this study, we proposed that rutin attenuated hypoxia-induced pulmonary artery smooth muscle cell (PASMC) proliferation by scavenging ROS. Immunofluorescence data showed that rutin decreased the production of ROS, which was mainly generated through mitochondria and NADPH oxidase 4 (Nox4) in pulmonary artery endothelial cells (PAECs). Western blot results provided further evidence on rutin increasing expression of Nox4 and hypoxia-inducible factor-1α (HIF-1α). Moreover, cell cycle analysis by flow cytometry indicated that proliferation of PASMCs triggered by hypoxia was also repressed by rutin. However, N-acetyl-L-cysteine (NAC), a scavenger of ROS, abolished or diminished the capability of rutin in repressing hypoxia-induced cell proliferation. These data suggest that rutin shows a potential benefit against the development of hypoxic pulmonary arterial hypertension by inhibiting ROS, subsequently preventing hypoxia-induced PASMC proliferation.
Highlights
Hypoxic pulmonary arterial hypertension (HPH) is a progressive disorder characterized by endothelial dysfunction, smooth muscle proliferation, intimal and/or medial layer remodeling, and right ventricular failure [1,2]
The results demonstrated that rutin abolished the production of Reactive oxygen species (ROS), generated through NADPH oxidase 4 (Nox4) and mitochondrial under hypoxic conditions in pulmonary artery endothelial cells (PAECs)
Rutin reduced the hypoxia-induced upregulation expression of Proliferating cell nuclear antigen (PCNA), whereas the inhibition effect was abolished by NAC (Figure 4). These results indicated that rutin inhibited hypoxia-induced PAECs migration and pulmonary artery smooth muscle cell (PASMC) proliferation, which may be through a ROS-dependent pathway
Summary
Hypoxic pulmonary arterial hypertension (HPH) is a progressive disorder characterized by endothelial dysfunction, smooth muscle proliferation, intimal and/or medial layer remodeling, and right ventricular failure [1,2]. Remodeling of pulmonary blood vessels results from the proliferation of pulmonary arterial smooth muscle cells (PASMCs) and pulmonary arterial endothelial cells (PAECs) migration [3,4]. Endothelial cells are generally recognized as the main regulators of vascular function. Imbalance between vasoconstriction and vasodilation is characterized by ECs dysfunction [5]. PAECs dysfunction is involved in the development of HPH by contribution to the disturbed migration and proliferation of PASMCs [6]. The exact causes of HPH are still under investigation
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