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 NH(2)-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.