Vascular interleukin-10 protects against LPS-induced vasomotor dysfunction.
We tested the hypotheses that 1) systemic IL-10, after adenoviral gene transfer, protects arteries from impaired relaxation produced by LPS; 2) local expression of IL-10 within the arterial wall protects against vasomotor dysfunction after LPS; and 3) IL-10 protects against vascular dysfunction mediated by inducible NO synthase (iNOS) after LPS. In IL-10-deficient (IL-10-/-) and wild-type (WT, IL-10+/+) mice, LPS in vivo impaired relaxation of arteries to acetylcholine and gene transfer of IL-10 improved responses to acetylcholine. Superoxide levels were elevated in arteries after LPS, and increased levels of superoxide were prevented by gene transfer of IL-10. In arteries incubated with a low concentration of LPS in vitro to eliminate systemic effects of LPS and IL-10 from nonvascular sources, responses to acetylcholine were impaired in IL-10-deficient mice and impairment was largely prevented by gene transfer in vitro of IL-10. In arteries from WT mice in vitro, the low concentration of LPS did not impair responses to acetylcholine. Thus IL-10 within the vessel wall protects against LPS-induced dysfunction. In IL-10-deficient mice, aminoguanidine, which inhibits iNOS, protected against vasomotor dysfunction after LPS. In arteries from iNOS-deficient mice, LPS did not impair responses to acetylcholine. These findings suggest that both systemic and local effects of IL-10 provide important protection of arteries against an inflammatory stimulus and that IL-10 decreases iNOS-mediated impairment of vasorelaxation after LPS.
Gunnett
Carol A
CA
Department of Internal Medicine, Univ. of Iowa Carver College of Medicine, Iowa City, IA 52242-6778, USA.
Lund
Donald D
DD
Faraci
Frank M
FM
Heistad
Donald D
DD
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects*; D002448:Cell Adhesion; D004730:Endothelium, Vascular; D018014:Gene Transfer Techniques; D006801:Humans; D066298:In Vitro Techniques; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology*; D007962:Leukocytes / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000172:deficiency / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D014652:Vascular Diseases / Q000139:chemically induced / Q000517:prevention & control*; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
D008070:Lipopolysaccharides; D014665:Vasodilator Agents; D016753:Interleukin-10; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D000109:Acetylcholine