title: Acute and Chronic Hyperglycemia Elicit JIP1/JNK-Mediated Endothelial Vasodilator Dysfunction of Retinal Arterioles.
abstract: Hyperglycemia, a hallmark of diabetes mellitus, is associated with retinal inflammation and impairment of endothelium-dependent nitric oxide (NO)-mediated dilation of retinal arterioles. However, molecular mechanisms involved in this diminished endothelial vasodilator function remain unclear. We examined whether inflammatory stress-activated kinases, c-Jun N-terminal kinase (JNK) and p38, contribute to retinal arteriolar dysfunction during exposure to acute and chronic hyperglycemia.
  
  
  
  Retinal arterioles were isolated from streptozocin-induced diabetic pigs (2 weeks; chronic hyperglycemia, 471 ± 23 mg/dL) or age-matched control pigs (euglycemia, 79 ± 5 mg/dL), and then cannulated and pressurized for vasoreactivity study. For acute hyperglycemia study, vessels from nondiabetic pigs were exposed intraluminally to high glucose (25 mM ≈ 450 mg/dL) for 2 hours, and normal glucose (5 mM ≈ 90 mg/dL) served as the control.
  
  
  
  Endothelium-dependent vasodilation to bradykinin was reduced in a similar manner after exposure to acute or chronic hyperglycemia. Administration of NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) nearly abolished vasodilations either in control (euglycemia and normal glucose) or hyperglycemic (acute and chronic) vessels. Treatment of either acute or chronic hyperglycemic vessels with JNK inhibitor SP600125 or JNK-interacting protein-1 (JIP1) inhibitor BI-78D3, but not p38 inhibitor SB203580, preserved bradykinin-induced dilation in an L-NAME-sensitive manner. By contrast, endothelium-independent vasodilation to sodium nitroprusside was unaffected by acute or chronic hyperglycemia.
  
  
  
  Activation of JIP1/JNK signaling in retinal arterioles during exposure to acute or chronic hyperglycemia leads to selective impairment of endothelium-dependent NO-mediated dilation. Therapeutic targeting of the vascular JNK pathway may improve retinal endothelial vasodilator function during early diabetes.
authors.affiliation: Department of Surgery, Baylor Scott & White Eye Institute, College of Medicine, Texas A&M Health Science Center, Temple, Texas, United States.
authors.forename: Travis W
authors.initials: TW
authors.lastname: Hein
authors.affiliation: Department of Surgery, Baylor Scott & White Eye Institute, College of Medicine, Texas A&M Health Science Center, Temple, Texas, United States.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Medical Physiology, College of Medicine, Texas A&M Health Science Center, Temple, Texas, United States.
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Surgery, Baylor Scott & White Eye Institute, College of Medicine, Texas A&M Health Science Center, Temple, Texas, United States 2Department of Medical Physiology, College of Medicine, Texas A&M Health Science Center, Temple, Texas, United States.
authors.forename: Lih
authors.initials: L
authors.lastname: Kuo
mesh_terms: D000208:Acute Disease; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001160:Arterioles / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D002908:Chronic Disease; D003921:Diabetes Mellitus, Experimental; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D006943:Hyperglycemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D012161:Retinal Artery / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013552:Swine; D014664:Vasodilation / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C490665:Mapk8ip protein, mouse; D009569:Nitric Oxide; D048031:JNK Mitogen-Activated Protein Kinases