Endogenous interleukin-10 inhibits angiotensin II-induced vascular dysfunction

Abstract

Angiotensin II (Ang II) produces inflammation and endothelial dysfunction in blood vessels. We tested the hypothesis that interleukin 10 (IL-10), an antiinflammatory cytokine, protects against Ang II-induced vascular dysfunction. Responses of carotid arteries from wild-type and IL-10-deficient mice (IL-10(-/-)) were examined in vitro after overnight incubation with vehicle or Ang II (1 nmol/L). In arteries from wild-type mice, acetylcholine (an endothelium-dependent agonist) produced relaxation that was not affected by Ang II. In contrast, relaxation to acetylcholine in arteries from IL-10(-/-) mice was reduced by >50% by Ang II (P<0.05) and this effect was prevented by a scavenger of superoxide. Vascular superoxide increased approximately 2-fold (P<0.05) after treatment with Ang II in IL-10(-/-) mice but not in wild-type. After systemic administration of Ang II (1.4 mg/kg per day for 10 days), Ang II produced modest impairment of endothelial function in wild-type mice but marked impairment in IL-10(-/-) mice (P<0.05) that was reversed by a superoxide scavenger. Increases in arterial pressure in response to Ang II were similar in wild-type and IL-10(-/-) mice. These findings provide the first evidence that endogenous IL-10 limits Ang II-mediated oxidative stress and vascular dysfunction both in vitro and in vivo suggesting that at least some of the protective effects of IL-10 may occur within the vessel wall.

Figure 1

Relaxation of the carotid artery in response to acetylcholine in wild-type (left panel; n=11) and IL-10 deficient (right panel; n=10) mice following overnight treatment with vehicle or Ang II (1 nmol/L). Values are means±SE. *P<0.05 vs vehicle.

Figure 2

Superoxide levels in aorta treated with vehicle or Ang II (1 nmol/L). Values are means±SE. n=11 wild-type (WT) and n=10 IL-10 deficient (KO). *P<0.05 vs vehicle.

Figure 3

Relaxation of the carotid artery in response to acetylcholine in IL-10 deficient mice following overnight treatment with vehicle, Ang II (1 nmol/L), or Ang II (1 nmol/L) and PEG-SOD. Values are means±SE (n=5). *P<0.05 vs vehicle.

Figure 4

Blood pressure in wild-type and IL-10 deficient mice (KO) under baseline conditions and following infusion of Ang II (1.4 mg/kg per day) for 10 days. Values are means±SE (n=6 and n=5 for wild-type infused with vehicle or Ang II, respectively; n=9 and n=10 for IL-10 deficient mice infused with vehicle or Ang II, respectively). *P<0.05 vs baseline.

Figure 5

Relaxation of the carotid artery in response to acetylcholine in wild-type (left panel; n=6) and IL-10 deficient (right panel; n=10) mice following infusion of vehicle or Ang II (1.4 mg/kg per day) for 10 days. Arteries from some of the IL-10 deficient mice treated with Ang II were treated with Tempol (n=4). Values are means±SE. *P<0.05 vs vehicle.

Figure 6

Relative expression levels of mRNA in aorta from control (WT) and IL-10 deficient mice (KO) following infusion of vehicle or Ang II (1.4 mg/kg per day) for 10 days. IL-6, TNFα, iNOS, and p22^phox were up-regulated by Ang II in WT and IL-10 KO mice (* P<0.05 versus vehicle). IL-6 was increased further in IL-10 KO mice treated with Ang II († P<0.05 versus WT treated with Ang II). Expression of TNFα and p22^phox tended to increase further in IL-10 KO mice (# 0.05<P<0.1 versus WT treated with Ang II). N = 6-9 in each group.