The adipokine chemerin increases vascular reactivity to ET-1 via activation of ERK1/2

Karla Neves1,2, Núbia Lobato3, Fernando Filgueira1, Ana Maria Oliveira1,2, Rita Tostes1. 1University of Sao Paulo, Pharmacology, 14049-900, Brazil, 2University of Sao Paulo, Pharmaceutical Sciences, 14040-903, Brazil, 3Federal University of Goias, Biological Sciences, 75800-000, Brazil.

Introduction: Obesity and cardiovascular diseases are associated with vascular dysfunction and elevated levels of pro-inflammatory cytokines. ET-1 is considered to play a major role on vascular dysfunction associated with these pathological conditions. Chemerin is a pro-inflammatory cytokine secreted by the adipose tissue. The mechanisms by which adipokines interfere with the vascular function as well as the effects of chemerin on vascular reactivity are not fully understood. Therefore, this study investigated the effects of chemerin on vascular reactivity and the mechanisms by which it modifies vascular function. We hypothesized that chemerin increases vascular reactivity to ET-1 via activation of MAPKs, a major signaling pathway activated by ET-1 in the vasculature.

Methods: Endothelium-intact and endothelium-denuded thoracic aortic rings (2-3mm) from 10-12 week-old male Wistar rats were used to record isometric contractions (DMT Wire Myograph; Krebs buffer pH 7,4; 37ºC; 5% CO2 - 95% O2). Vessels were incubated with chemerin (0.5ng/mL or 5ng/mL; for 1 or 24 h) and cumulative responses to ET-1 (10-12 - 3x10-8 M) were determined, in the presence of vehicle (distilled water) or ERK1/2 inhibitor (PD 98059, 1µM, 30 min before the incubation with chemerin). Vascular protein expression of ERK1/2 was also determined in aortic rings incubated with chemerin (0.5ng/mL; 1 and 24 h) plus ET-1 (10-7 M; 10 min)

Results: Chemerin (0.5ng/mL; n = 5-6) augmented ET-1-induced vasoconstriction [pD2 = 1h: 10.5±0,2 vs. 9,1±0,04 vehicle (PBS 0,1% BSA) (p<0,05); 24 h: 10.9±0,1 vs. 8.7±0,02 vehicle (p<0,05). Endothelium removal further augmented chemerin effects. The potentiation of ET-1-induced vasoconstriction by chemerin (0,5ng/mL, 1h) was abolished by ERK1/2 inhibition [pD2 = 9.1±0,6 (p<0,05)] (see Figure). Chemerin (0,5ng/mL) induced vascular ERK1/2 phosphorylation arbitrary units and also potentiated ET-1 induced ERK1/2 phosphorylation arbitrary units

Conclusions: The adipokine chemerin increases vascular contractile responses to ET-1 via activation of ERK1/2 signaling. These effects may contribute to obesity- and ET-1-associated vascular dysfunction.

Figure 1. Cumulative concentration-response curves to ET-1 in endothelium-intact thoracic aortas incubated with chemerin (1 h) plus vehicle or Pd98059 (ERK1/2 inhibitor, 1 µM).