title: Aging impairs PI3K/Akt signaling and NO-mediated dilation in soleus muscle feed arteries.
abstract: We tested the hypothesis that impaired nitric oxide (NO)-mediated, endothelium-dependent dilation in aged soleus muscle feed arteries (SFA) is due to an age-related decline in the potential for PI3-kinase (PI3K)/protein kinase B (Akt)-dependent phosphorylation of endothelial NO synthase (eNOS) on serine residue 1177 (p-eNOS(ser1177)). SFA from young (4 months) and old (24 months) Fischer 344 rats were cannulated for examination of endothelium-dependent [flow or acetylcholine (ACh)] and endothelium-independent [sodium nitroprusside (SNP)] vasodilator function. To determine the mechanism by which aging affected vasodilation to flow and ACh, vasodilator responses were assessed in the presence of N (ω)-nitro-L-arginine (L-NNA, to inhibit NOS), LY-294002 (to inhibit PI3K), or 1L6-hydroxymethyl-chiro-inositol-2-(R)-2-O-methyl-3-O-octadecyl-sn-glycerocarbonate (AktI, to inhibit Akt). Flow- and ACh-induced vasodilator responses were significantly impaired in old SFA, whereas endothelium-independent dilation to SNP was not compromised. Age-group differences in flow- and ACh-induced dilations were abolished in the presence of L-NNA, LY-294002, or AktI. In a separate experiment, SFA were cannulated and stimulated with ACh (10(-4) M, 3 min), flow (60 μl/min, 5 min), or remained unstimulated (3 min). SFA were removed from the pipettes and immunoblot analysis was used to assess ACh- and flow-stimulated phosphorylation of eNOS on ser(1177). Stimulation with ACh or flow increased phosphorylation of eNOS on ser(1177) in young (not old) SFA. Preincubation of young SFA with LY-294002, abolished the ACh-induced phosphorylation of eNOS in young SFA. Collectively, these results indicate that impaired NO-mediated, endothelium-dependent dilation in old SFA is due, in part, to an impaired potential for PI3K/Akt-dependent phosphorylation of eNOS on ser(1177).
authors.affiliation: Department of Health and Kinesiology, Texas A&M University, 154C Read Building, MS 4243, College Station, TX 77843-4243, USA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Trott
authors.forename: Meredith J
authors.initials: MJ
authors.lastname: Luttrell
authors.forename: John W
authors.initials: JW
authors.lastname: Seawright
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Woodman
mesh_terms: D000375:Aging; D000818:Animals; D001158:Arteries / Q000033:anatomy & histology / Q000502:physiology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006614:Hindlimb / Q000098:blood supply; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply*; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction; D014664:Vasodilation
chemical_list: D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C496316:Nos3 protein, rat
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