title: Endothelial Dysfunction in Human Diabetes Is Mediated by Wnt5a-JNK Signaling.
abstract: OBJECTIVE
  Endothelial dysfunction is linked to insulin resistance, inflammatory activation, and increased cardiovascular risk in diabetes mellitus; however, the mechanisms remain incompletely understood. Recent studies have identified proinflammatory signaling of wingless-type family member (Wnt) 5a through c-jun N-terminal kinase (JNK) as a regulator of metabolic dysfunction with potential relevance to vascular function. We sought to gain evidence that increased activation of Wnt5a-JNK signaling contributes to impaired endothelial function in patients with diabetes mellitus.
  
  
  RESULTS
  We measured flow-mediated dilation of the brachial artery and characterized freshly isolated endothelial cells by protein expression, eNOS activation, and nitric oxide production in 85 subjects with type 2 diabetes mellitus (n=42) and age- and sex-matched nondiabetic controls (n=43) and in human aortic endothelial cells treated with Wnt5a. Endothelial cells from patients with diabetes mellitus displayed 1.3-fold higher Wnt5a levels (P=0.01) along with 1.4-fold higher JNK activation (P<0.01) without a difference in total JNK levels. Higher JNK activation was associated with lower flow-mediated dilation, consistent with endothelial dysfunction (r=0.53, P=0.02). Inhibition of Wnt5a and JNK signaling restored insulin and A23187-mediated eNOS activation and improved nitric oxide production in endothelial cells from patients with diabetes mellitus. In endothelial cells from nondiabetic controls, rWnt5a treatment inhibited eNOS activation replicating the diabetic endothelial phenotype. In human aortic endothelial cells, Wnt5a-induced impairment of eNOS activation and nitric oxide production was reversed by Wnt5a and JNK inhibition.
  
  
  CONCLUSIONS
  Our findings demonstrate that noncanonical Wnt5a signaling and JNK activity contribute to vascular insulin resistance and endothelial dysfunction and may represent a novel therapeutic opportunity to protect the vasculature in patients with diabetes mellitus.
authors.affiliation: From the Whitaker Cardiovascular Institute, Department of Medicine, Boston University School of Medicine, MA.
authors.forename: Rosa
authors.initials: R
authors.lastname: Bretón-Romero
authors.affiliation: From the Whitaker Cardiovascular Institute, Department of Medicine, Boston University School of Medicine, MA.
authors.forename: Bihua
authors.initials: B
authors.lastname: Feng
authors.affiliation: From the Whitaker Cardiovascular Institute, Department of Medicine, Boston University School of Medicine, MA.
authors.forename: Monika
authors.initials: M
authors.lastname: Holbrook
authors.affiliation: From the Whitaker Cardiovascular Institute, Department of Medicine, Boston University School of Medicine, MA.
authors.forename: Melissa G
authors.initials: MG
authors.lastname: Farb
authors.affiliation: From the Whitaker Cardiovascular Institute, Department of Medicine, Boston University School of Medicine, MA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Fetterman
authors.affiliation: From the Whitaker Cardiovascular Institute, Department of Medicine, Boston University School of Medicine, MA.
authors.forename: Erika A
authors.initials: EA
authors.lastname: Linder
authors.affiliation: From the Whitaker Cardiovascular Institute, Department of Medicine, Boston University School of Medicine, MA.
authors.forename: Brittany D
authors.initials: BD
authors.lastname: Berk
authors.affiliation: From the Whitaker Cardiovascular Institute, Department of Medicine, Boston University School of Medicine, MA.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Masaki
authors.affiliation: From the Whitaker Cardiovascular Institute, Department of Medicine, Boston University School of Medicine, MA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Weisbrod
authors.affiliation: From the Whitaker Cardiovascular Institute, Department of Medicine, Boston University School of Medicine, MA.
authors.forename: Elica
authors.initials: E
authors.lastname: Inagaki
authors.affiliation: From the Whitaker Cardiovascular Institute, Department of Medicine, Boston University School of Medicine, MA.
authors.forename: Noyan
authors.initials: N
authors.lastname: Gokce
authors.affiliation: From the Whitaker Cardiovascular Institute, Department of Medicine, Boston University School of Medicine, MA.
authors.forename: Jose J
authors.initials: JJ
authors.lastname: Fuster
authors.affiliation: From the Whitaker Cardiovascular Institute, Department of Medicine, Boston University School of Medicine, MA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
authors.affiliation: From the Whitaker Cardiovascular Institute, Department of Medicine, Boston University School of Medicine, MA. nhamburg@bu.edu.
authors.forename: Naomi M
authors.initials: NM
authors.lastname: Hamburg
mesh_terms: D000328:Adult; D000368:Aged; D001916:Brachial Artery / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D016022:Case-Control Studies; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology* / Q000503:physiopathology; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D060449:Wnt Signaling Pathway / Q000187:drug effects; D000071818:Wnt-5a Protein
chemical_list: D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D048031:JNK Mitogen-Activated Protein Kinases
keywords: brachial artery; endothelium; inflammation; nitric oxide; type 2 diabetes mellitus