Journal
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
Volume 13, Issue 9A, Pages 2899-2910Publisher
WILEY
DOI: 10.1111/j.1582-4934.2008.00416.x
Keywords
calcium homeostasis; calpain activation; endothelium dysfunction; eNOS; heavily oxidized and glycated-LDL (HOG-LDL); nitric oxide
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Funding
- NIH [HL079584, HL074399, HL080499, HL089920, HL55782, HL80921]
- American Diabetes Association [1-05-RA-74]
- Juvenile Diabetes Research Foundation
- Oklahoma Center for Advancement of Science and Technology (OCAST)
- Travis Endowed Chair in Endocrinology
- University of Oklahoma Health Sciences Center
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Oxidation and glycation of low-density lipoprotein (LDL) promote vascular injury in diabetes; however, the mechanisms underlying this effect remain poorly defined. The present study was conducted to determine the effects of 'heavily oxidized' glycated LDL (HOG-LDL) on endothelial nitric oxide synthase (eNOS) function. Exposure of bovine aortic endothelial cells with HOG-LDL reduced eNOS protein levels in a concentration- and time-dependent manner, without altering eNOS mRNA levels. Reduced eNOS protein levels were accompanied by an increase in intracellular Ca2+, augmented production of reactive oxygen species (ROS) and induction of Ca2+-dependent calpain activity. Neither eNOS reduction nor any of these other effects were observed in cells exposed to native LDL. Reduction of intracellular Ca2+ levels abolished eNOS reduction by HOG-LDL, as did pharmacological or genetic through calcium channel blockers or calcium chelator BAPTA or inhibition of NAD(P)H oxidase (with apocynin) or inhibition of calpain (calpain 1-specific siRNA). Consistent with these results, HOG-LDL impaired acetylcholine-induced endothelium-dependent vasorelaxation of isolated mouse aortas, and pharmacological inhibition of calpain prevented this effect. HOG-LDL may impair endothelial function by inducing calpain-mediated eNOS degradation in a ROS- and Ca2+-dependent manner.
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