Abstract. Diabetic cardiovascular diseases are characterized by progressive hyperglycemia, which results in excessive produc- tion of oxidative stress and pro‐inflammatory cytokines. Cystic fibrosis (CF) is characterized by chronic inflammation due to mutations in CF transmembrane conductance regula

Diabetic cardiovascular diseases are characterized by progressive hyperglycemia, which results in excessive production of oxidative stress and pro‐inflammatory cytokines. Cystic fibrosis (CF) is characterized by chronic inflammation due to mutations in CF transmembrane conductance regulator (CFTR). However, little information is available about the role of CFTR in hyperglycemia-induced endothelial cell oxidative stress and inflammation. In the present study, a high glucose‐treatment was applied in human umbilical vein endothelial cells with CFTR overexpression or inhibition, and the oxidative and inflammatory characteristics were measured. It was shown that CFTR protein and mRNA expression were reduced by glucose in a concentration‐dependent manner. Overexpression of CFRT via adenoviral infection significantly inhibited the production of reactive oxygen species and inflammatory biomediators induced by high glucose. Conversely, pharmacological inhibition of CFTR led to the opposite effects. Mechanistically, nuclear factor‐κB (NF‐κB) and mitogen‐activated protein kinase (MAPK) signaling were activated following high glucose treatment, which were inhibited by CFTR overexpression and enhanced by CFTR inhibition. The pro‐inflammatory effect of CFTR inhibition was abolished by pharmacological inhibition of the NF-κB or MAPK pathways. Moreover, inhibition of MAPK abrogated CFTR inhibition-induced NF-κB nuclear translocation, whereas NF-κB inhibitor produced no effects on MAPK activation. Additionally, antioxidant treatment inhibited the high glucose-induced decrease in CFTR expression and the increase in inflammatory responses. Collectively, these findings revealed that CFTR attenuates high glucose-induced endothelial cell oxidative stress and inflammation through inactivation of NF-κB and MAPK signaling, indicating that elevation of CFRT expression may be a novel strategy in preventing endothelial dysfunction in diabetes. Introduction Diabetes is a chronic macrovascular and microvascular disease induced by hyperglycemia, affecting millions of individuals globally (1). Approximately 80% of diabetes‐related mortality is caused by cardiovascular diseases, including atherosclerosis, hypertension and cardiomyopathy (2). Moreover, endothelial dysfunction, characterized by inflammation and oxidative stress, is one of the most common causes of morbidity and mortality in diabetes‐related cardiovascular diseases (1,3). It is known that inflammation serves a critical role in the development and progression of diabetes (3,4). An excessive or inappropriate production of pro‐inflammatory cytokines, such as interleukin‐1β (IL‐1β), could induce the expression of inflammatory mediators [e.g., intercellular adhesion molecule‐1 (ICAM‐1) and vascular cell adhesion molecule‐1 (VCAM‐1)] as a positive feedback mechanism and subsequently result in endothelial cell activation, which eventually leads to endothelial dysfunction (1,5). In addition, high glucose-induced oxidative stress, primarily associated with the production of reactive oxygen species (ROS), also serves a pivotal role in endothelial dysfunction during the development of diabetes (6). ROS function as signaling molecules to activate a variety of stress pathways and inflammatory pathways, which in turn further enhance inflammatory responses (7,8). Furthermore, inhibition of ROS with antioxidant agents can attenuate inflammation and rescue endothelial cells (9). However, the mechanisms by which high glucose induces inflammation and oxidative stress are not fully understood. Mounting evidence has suggested that nuclear factor-κB (NF‐κB) and mitogen‐activated protein kinase (MAPK) signaling are the classical pathways to regulate ROS production and inflammation (10‐12). Activation of these pathways can increase ROS production and accelerate the inflammation progress, and thus cause endothelial dysfunction (13). It is worthy to note that high glucose can induce NF-κB nuclear translocation, MAPK activation and inflammatory biomediator production in the endothelial cells of diabetic patients (14). Therefore, these signaling pathways and inflammation may be pivotal pathogenic mechanisms underlying endothelial dysfunction caused by hyperglycemia. Cystic fibrosis (CF) is a common autosomal recessive disorder due to mutations of the CF transmembrane conductance regulator (CFTR) gene, which is located on the long CFTR ameliorates high glucose-induced oxidative stress and inflammation by mediating the NF-κB and MAPK signaling pathways in endothelial cells YANG FEI, LIQIN SUN, CHUNGANG YUAN, MIN JIANG, QINHUA LOU and YAN XU Department of Endocrinology, Fuyang First People's Hospital, Hangzhou, Zhejiang 311400, P.R. China Received August 1, 2016; Accepted January 24, 2018 DOI: 10.3892/ijmm.2018. 3547 Correspondence to: Ms. Yang Fei, Department of Endocrinology, Fuyang First People's Hospital, 429 Beihuan Road, Fuyang, Hangzhou, Zhejiang 311400, P.R. China E‐mail: fy_satish@163.com