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Invest Ophthalmol Vis Sci. 2016 Aug 1;57(10):4333-40. doi: 10.1167/iovs.16-19990.

Acute and Chronic Hyperglycemia Elicit JIP1/JNK-Mediated Endothelial Vasodilator Dysfunction of Retinal Arterioles.

Author information

1
Department of Surgery, Baylor Scott & White Eye Institute, College of Medicine, Texas A&M Health Science Center, Temple, Texas, United States.
2
Department of Medical Physiology, College of Medicine, Texas A&M Health Science Center, Temple, Texas, United States.
3
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.

Abstract

PURPOSE:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

PMID:
27556216
PMCID:
PMC5015966
DOI:
10.1167/iovs.16-19990
[Indexed for MEDLINE]
Free PMC Article

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