Resistin decreases expression of endothelial nitric oxide synthase through oxidative stress in human coronary artery endothelial cells

Abstract

Resistin decreases expression of endothelial nitric oxide synthase through oxidative stress in human coronary artery endothelial cells. Am J Physiol Heart Circ Physiol 299: H193-H201, 2010. First published April 30, 2010 doi:10.1152/ajpheart.00431.2009.-Resistin is a newly discovered adipocyte-derived cytokine that may play an important role in insulin resistance, diabetes, adipogenesis, inflammation, and cardiovascular disease. However, it is largely unknown whether resistin impairs endothelial functions by affecting the endothelial nitric oxide synthase (eNOS) system. In this study, we determined the effect of human recombinant resistin protein on eNOS expression and regulation in human coronary artery endothelial cells (HCAECs). When cells were treated with clinically relevant concentrations of resistin (40 or 80 ng/ml) for 24 h, the levels of eNOS mRNA, protein, and activity and eNOS mRNA stability were significantly reduced. Cellular nitric oxide levels were also decreased. In addition, the cellular levels of reactive oxygen species (ROS), including superoxide anion, were significantly increased in resistin-treated HCAECs. Mitochondrial membrane potential and the activities of catalase and superoxide dismutase were reduced. Three antioxidants, seleno-L-methionine, ginsenoside Rb1, and MnTBAP (superoxide dismutase mimetic), effectively blocked resistin-induced eNOS downregulation. Meanwhile, resistin activated the mitogen-activated protein kinases p38 and c-Jun NH2-terminal kinase (JNK), and the specific p38 inhibitor SB-239063 effectively blocked resistin-induced ROS production and eNOS downregulation. Furthermore, immunoreactivity of resistin was increased in atherosclerotic regions of human aorta and carotid arteries. Thus resistin directly induces eNOS downregulation through overproduction of ROS and activation of p38 and JNK in HCAECs. Resistin-induced mitochondrial dysfunction and imbalance in cellular redox enzymes may be the underlying mechanisms of oxidative stress.

Expression and effect of resistin on bovine and rat granulosa cell steroidogenesis and proliferation

“…This hormone has been shown to modulate phosphorylation of MAPK (ERK1/2, p38, and JNK; Di Simone et al 2009, Chen et al 2010, AKT (Palanivel et al 2006), and AMPK (Satoh et al 2004) in different cell types. These signaling pathways have been described to play a role in steroidogenesis and/or proliferation of GCs in response to various hormones such as FSH, IGF1, and insulin, as well as more recently to some adipokines including leptin and adiponectin (Moore et al 2001, Kayampilly & Menon 2004, Tosca et al 2005, Yu et al 2005, Ryan et al 2008, Kayampilly & Menon 2009).…”

Relationship of resistin levels with endometrial cancer risk

“…This contrast could be caused by fact, that human and mouse RETN genes share only 53% homology, therefore their functions may differ between them [11] and other roles of RETN may exist in human. Although the exact function of resistin in human is still not known, increased resistin levels have been associated with coronary heart disease [12][13][14][15] and considered as a risk factor in gastric, colon and breast cancer [16][17][18][19], recently. The purpose of this case-control study was to determine the relationship between serum circulating resistin levels and resistin gene -420C>G (rs3219175) variant in endometrial cancer patients.…”

High Serum Resistin Levels in Coronary Artery Ectasia

“…Resistin impairs endothelial functions and causes the uptake of oxidized low density lipoprotein cholesterol and the formation of foam cells after being released by macrophages [39][40][41] . Resistin upregulates the release of adhesion molecules, increases the secretion of proinflammatory factors such as tumour necrosis factor-α, interleukin-6, interleukin-12, nitric oxide, endothelin-1 and matrix metalloproteinases and induces angiogenesis by increasing vascular epithelial growth factor (42)(43)(44)(45)(46)(47) . It has also been reported that resistin exerts a prothrombotic effect by inducing the secretion of tissue factor (48) .…”