title: A novel mechanism for vascular insulin resistance in normotensive young SHRs: hypoadiponectinemia and resultant APPL1 downregulation.
abstract: Vascular insulin resistance contributes to elevated peripheral vascular resistance and subsequent hypertension. Clinical observation showed that lower plasma adiponectin concentration is significantly associated with hypertension. This study was aimed to determine whether hypoadiponectinemia induces vascular insulin resistance before systemic hypertension and the underlying mechanisms. Four-week-old young spontaneously hypertensive rats (ySHRs, normotensive) and adiponectin knockout (KO; APN(-/-)) mice were used to evaluate the role of hypoadiponectinemia in insulin-induced vasodilation of resistance vessels. ySHRs showed significant vascular insulin resistance as evidenced by the blunted vasorelaxation response to insulin in mesenteric arterioles compared with that of age-matched Wistar-Kyoto controls. Serum adiponectin and mesenteric arteriolar APPL1 (an adaptor protein that mediates adiponectin signaling) expression of ySHRs were significantly reduced. In addition, Akt and endothelial NO synthase phosphorylation and NO production in arterioles were markedly reduced, whereas extracellular signal-regulated protein kinases 1/2 (ERK1/2) phosphorylation and endothelin-1 secretion were augmented in ySHRs. APN(-/-) mice showed significantly decreased APPL1 expression and vasodilation evoked by insulin. More importantly, treatment of ySHRs in vivo with the globular domain of adiponectin for 1 week increased APPL1 expression and insulin-induced vasodilation, and restored the balance between insulin-stimulated endothelial vasodilator NO and vasoconstrictor endothelin-1. In cultured human umbilical vein endothelial cells, globular domain of adiponectin upregulated APPL1 expression. Suppression of APPL1 expression with small interfering RNA markedly blunted the globular domain of adiponectin-induced insulin sensitization as evidenced by reduced Akt/endothelial NO synthase and potentiated ERK1/2 phosphorylations. In conclusion, hypoadiponectinemia induces APPL1 downregulation in the resistance vessels, contributing to the development of vascular insulin resistance by differentially modulating the Akt/endothelial NO synthase/NO and ERK1/2/endothelin-1 pathways in vascular endothelium in normotensive ySHRs.
authors.affiliation: Department of Physiology, Xijing Hospital, Fourth Military Medical University, Xi’an, China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Xing
authors.forename: Wenjun
authors.initials: W
authors.lastname: Yan
authors.forename: Peilin
authors.initials: P
authors.lastname: Liu
authors.forename: Lele
authors.initials: L
authors.lastname: Ji
authors.forename: Youyou
authors.initials: Y
authors.lastname: Li
authors.forename: Lu
authors.initials: L
authors.lastname: Sun
authors.forename: Ling
authors.initials: L
authors.lastname: Tao
authors.forename: Haifeng
authors.initials: H
authors.lastname: Zhang
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000097:blood*; D052242:Adiponectin / Q000097:blood* / Q000172:deficiency / Q000235:genetics; D000818:Animals; D001160:Arterioles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D019332:Endothelin-1 / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000503:physiopathology*; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D008661:Metabolism, Inborn Errors / Q000097:blood / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000097:blood*; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D015398:Signal Transduction / Q000502:physiology; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014655:Vascular Resistance / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D052242:Adiponectin; C515694:Appl1 protein, rat; D019332:Endothelin-1; D007328:Insulin; D009419:Nerve Tissue Proteins; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt