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Interleukin-10 attenuates vascular responses to endothelin-1 via effects on ERK1/2-dependent pathway

¹Department of Physiology, Medical College of Georgia, Augusta, Georgia; ²Department of Pharmacology, University of Sao Paulo, Sao Paulo, SP, Brazil; and ³Kidney Research Centre, University of Ottawa, Ottawa, Ontario, Canada

Submitted 10 March 2008 ; accepted in final form 10 December 2008

Interleukin-10 (IL-10) is an anti-inflammatory cytokine with protective actions on the vasculature. On the other hand, endothelin (ET)-1 has potent vasoconstrictor, mitogenic, and proinflammatory activities, which have been implicated in the pathophysiology of a number of cardiovascular diseases. We hypothesized that, in a condition where ET-1 expression is upregulated, i.e., on infusion of TNF-, IL-10 confers vascular protection from ET-1-induced injury. Aortic rings and first-order mesenteric arteries from male C57BL/6 (WT) and IL-10-knockout (IL-10^–/–) mice were treated with human recombinant TNF- (220 ng·kg^–1·day^–1) or vehicle (saline) for 14 days. TNF- infusion significantly increased blood pressure in IL-10^–/–, but not WT, mice. TNF- augmented vascular ET-1 mRNA expression in arteries from WT and IL-10^–/– mice. ET type A (ET_A) receptor expression was increased in arteries from IL-10^–/– mice, and TNF- infusion did not change vascular ET_A receptor expression in control or IL-10^–/– mice. Aorta and mesenteric arteries from TNF--infused IL-10^–/– mice displayed increased contractile responses to ET-1, but not the ET type B receptor agonist IRL-1620. The ET_A receptor antagonist atrasentan completely abolished responses to ET-1 in aorta and mesenteric vessels, whereas the ERK1/2 inhibitor PD-98059 abrogated increased contractions to ET-1 in arteries from TNF--infused IL-10^–/– mice. Infusion of TNF-, as well as knockdown of IL-10 (IL-10^–/–), induced an increase in total and phosphorylated ERK1/2. These data demonstrate that IL-10 counteracts ET_A-mediated vascular responses to ET-1, as well as activation of the ERK1/2 pathway.

tumor necrosis factor-; vascular reactivity; blood pressure

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