Abstract 101: Chemerin, A Novel Adipokine, Regulates Human Vascular Cell Function Through Redox-sensitive Processes Involving NADPH Oxidase 1/4 And Endothelial Nitric Oxide Sinthase.
Adipose tissue produces many adipokines, including chemerin, a chemoattractant for inflammatory cells that mediates its effects through chemokine-like receptor 1 (CMKLR1). Chemerin has been implicated in endothelial dysfunction and vascular inflammation, hallmarks of vascular injury in hypertension. These pathological processes are induced by reactive oxygen species (ROS). How chemerin regulates ROS is unknown. We postulated that chemerin, through redox-sensitive mechanisms, influences signalling in vascular cells. Human vascular smooth muscle cells (HVSMCs) and microvascular endothelial cells (HMECs) were studied. HVSMCs and HMECs were stimulated with recombinant chemerin (50ng/ml). eNOS and MAPK activation were assessed by immmunoblotting, ROS generation by chemiluminescence and nitric oxide (NO) levels by DAF-FM fluorescence. mRNA expression of Nox 1, Nox 4 and inflammatory markers was assessed by real time PCR. Chemerin stimulated ROS generation in HVSMCs (1 h - 21% increase; 8 h - 41% increase) and HMECs(1 h - 54% increase; 24 h - 76% increase, p<0.05 vs vehicle), effects blocked by Nox1/4 inhibitor (GKT137831) and Nox1 inhibitor (ML171). Chemerin also increased phosphorylation of ERK1/2 (43% and 62%), p38MAPK (18% and 25%) and JNK (59% and 73%) in HVSMCs and HMECs respectively. eNOS phosphorylation (Ser1177, activation site) was decreased by chemerin in HMECs (45% decrease), while phosphorylation at nhibitory site, Thr495, was increased (72%). In parallel, chemerin decreased NO levels in HMECs by 33%. Finally, chemerin increased IL-6 (290%), MCP-1 (64%), VCAM-1 (210%) and ICAM-1 (130%) mRNA levels in HVSMCs. Nox 1 (49%) and Nox 4 (67%) mRNA levels were increased in HVSMCs stimulated with chemerin. In conclusion in human vascular cells, chemerin stimulates ROS generation and reduces NO formation, through Nox1/4 activation and eNOS inhibition respectively. These processes were associated with increased redox-sensitive MAPK signaling and inflammation. Our study identifies chemerin as a new vasoactive factor, that plays an important role in vascular injury and dysfunction, which may be particularly important in the context of increased adipocyte-derived chemerin, such as in obesity, metabolic syndrome and hypertension.
Author Disclosures: K.B. Neves: None. R.A.M. Lopes: None. A.D.C. Nguyen: None. N.S. Lobato: None. A. Oliveira: None. A.C. Montezano: None. R.C. Tostes: None. R.M. Touyz: None.
- © 2014 by American Heart Association, Inc.