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

Fernanda R.C. Giachini, Saiprasad M. Zemse, Fernando S. Carneiro, Victor V. Lima, Zidonia N. Carneiro, Glaucia E. Callera, Adviye Ergul, R Clinton Webb, Rita C. Tostes

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18 Scopus citations

Abstract

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-α, 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-α (220 ng• kg -1 • day -1) or vehicle (saline) for 14 days. TNF-α infusion significantly increased blood pressure in IL-10 -/-, but not WT, mice. TNF-α 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-α infusion did not change vascular ETA receptor expression in control or IL-10 -/- mice. Aorta and mesenteric arteries from TNF-α-infused IL-10 -/- mice displayed increased contractile responses to ET-1, but not the ET type B receptor agonist IRL-1620. The ETA 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-α-infused IL-10 -/- mice. Infusion of TNF-α, as well as knockdown of IL-10 (IL-10 -/-), induced an increase in total and phosphor- ylated ERK1/2. These data demonstrate that IL-10 counteracts ETA- mediated vascular responses to ET-1, as well as activation of the ERK1/2 pathway.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume296
Issue number2
DOIs
Publication statusPublished - Feb 1 2009

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Keywords

  • Blood pressure
  • Tumor necrosis factor-α
  • Vascular reactivity

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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