title: Suppressed G-protein-coupled receptor kinase 2 activity protects female diabetic-mouse aorta against endothelial dysfunction.
abstract: OBJECTIVE
  Pre-menopausal women have less cardiovascular disease and lower cardiovascular morbidity and mortality than men the same age. Previously, we noted in mice that G-protein-coupled receptor kinase 2 (GRK2) negatively regulates the Akt/eNOS pathway in male diabetic aortas and that endothelial function via the Akt/eNOS pathway is less affected in female diabetic aortas. The cellular mechanisms underlying these sex differences remain unclear. We aimed to investigate the ways in which GRK2 might modulate vascular functions in male and female diabetic mice (DM).
  
  
  METHODS
  Vascular functions were examined in aortic rings. GRK2, β-arrestin 2 and Akt/eNOS-signalling-pathway protein levels and activities were assayed by Western blotting.
  
  
  RESULTS
  Phenylephrine-induced contraction was greater, while both clonidine-induced and insulin-induced relaxations were weaker (vs. male controls), in aortas from male type 2 DM, suggesting impairments of the Akt/eNOS pathway and α-adrenoceptor function. GRK2-inhibitor reversed only the impairment in Akt/eNOS-pathway-mediated relaxation in male DM. Increases in GRK2 activity, GRK2 expression in the membrane, plasma Ang II and systolic blood pressure were seen in male DM (vs. male controls) but not in female DM; these increases were attenuated by GRK2-inhibitor treatment. Repeatedly obtaining clonidine concentration-response curves led to reduced relaxation in male and in female DM aortas, indicating similar desensitization between female DM and male DM. This effect was reversed by GRK2-inhibitor in both sexes.
  
  
  CONCLUSIONS
  GRK2 plays a key role in modulating the aortic vasodilator effect of clonidine by selectively affecting the Akt/eNOS pathway. This action of GRK2 is more powerful in male than in female DM.
authors.affiliation: Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Taguchi
authors.forename: T
authors.initials: T
authors.lastname: Matsumoto
authors.forename: K
authors.initials: K
authors.lastname: Kamata
authors.forename: T
authors.initials: T
authors.lastname: Kobayashi
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D003000:Clonidine / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012727:Sex Characteristics; D015398:Signal Transduction / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2; D003000:Clonidine