Journal
CELLULAR PHYSIOLOGY AND BIOCHEMISTRY
Volume 35, Issue 1, Pages 364-373Publisher
KARGER
DOI: 10.1159/000369702
Keywords
NOX4; ROS; ICAM-1; Acetoacetate, and type 1 diabetes
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Funding
- NIDDK
- Office of Dietary Supplements
- National Institutes of Health [RO1 AT007442]
- Malcolm Feist Endowed Chair in Diabetes
- Malcolm Feist Cardiovascular Research Fellowship from LSUHSC, Shreveport
- National Center for Complementary & Integrative Health [R01AT007442] Funding Source: NIH RePORTER
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Background/Aims: The incidence of developing microvascular dysfunction is significantly higher in type 1 diabetic (T1D) patients. Hyperketonemia (acetoacetate, beta-hydroxybutyrate) is frequently found along with hyperglycemia in T1D. Whether hyperketonemia per se contributes to the excess oxidative stress and cellular injury observed in T1D is not known. Methods: HUVEC were treated with ketones in the presence or absence of high glucose for 24 h. NOX4 siRNA was used to specifically knockdown NOX4 expression in HUVEC. Results: Ketones alone or in combination with high glucose treatment cause a significant increase in oxidative stress, ICAM-1, and monocyte adhesivity to HUVEC. Using an antisense approach, we show that ketone induced increases in ROS, ICAM-1 expression, and monocyte adhesion in endothelial cells were prevented in NOX4 knockdown cells. Conclusion: This study reports that elevated levels of ketones upregulate NOX, contributing to increased oxidative stress, ICAM-1 levels, and cellular dysfunction. This provides a novel biochemical mechanism that elucidates the role of hyperketonemia in the excess cellular injury in T1D. New drugs targeting inhibition of NOX seems promising in preventing higher risk of complications associated with T1D. Copyright (C) 2015 S. Karger AG, Basel
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