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(Circulation Research. 2006;99:191.)
© 2006 American Heart Association, Inc.

Cellular Biology

Novel Effect of Oxidized Low-Density Lipoprotein

Cellular ATP Depletion via Downregulation of Glyceraldehyde-3-Phosphate Dehydrogenase

Sergiy Sukhanov, Yusuke Higashi, Shaw-Yung Shai, Hiroyuki Itabe, Koichi Ono, Sampath Parthasarathy, Patrick Delafontaine

From the Cardiology Section (S.S., Y.H., S.-Y.S, P.D.), Department of Medicine, Tulane University, New Orleans, La; Department of Biological Chemistry (H.I.), Showa University, Tokyo, Japan; Innoshima City Medical Associated Hospital (K.O.), Japan; and Pathology Department (S.P.), Louisiana State University, New Orleans.

Correspondence to Patrick Delafontaine, Cardiology Section, Department of Medicine, TUHSC, 1430 Tulane Ave, SL-48, New Orleans, LA 70112-2699. E-mail pdelafon{at}tulane.edu

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a classical glycolytic enzyme that is involved in cellular energy production and has important housekeeping functions. We used the natural prooxidant and proatherogenic molecule oxidized low-density lipoprotein (OxLDL) to determine a potential link between OxLDL-promoted oxidative stress, GAPDH expression, and smooth muscle cell energy metabolism. OxLDL but not native LDL (nLDL) produced a 60% to 100% dose- and time-dependent reduction of GAPDH protein. OxLDL increased reactive oxygen species (ROS) formation, including rapid elevation of H₂O₂ levels. OxLDL decreased intracellular catalase expression, likely contributing to the increase in H₂O₂. Antioxidants, anti-CD36 receptor antibody, NADPH oxidase, or lipoxygenase blockers decreased OxLDL-specific ROS and prevented GAPDH downregulation. 12/15-Lipoxygenase or p47phox deficiency resulted in attenuation of GAPDH downregulation, but 5-lipoxygenase suppression had no effect. OxLDL or exogenous H₂O₂ oxidized GAPDH thiols, decreasing GAPDH protein half-life and increasing GAPDH sensitivity to proteasome-mediated protein degradation in vitro. OxLDL- or small interfering RNA–specific downregulation of GAPDH resulted in 65% reduction in glycolysis rate and 82% decrease in ATP levels. In conclusion, our data demonstrate that OxLDL downregulated GAPDH via a H₂O₂-dependent decrease in protein stability. GAPDH protein damage resulted in marked depletion of cellular ATP levels. Our data have important implications for understanding the metabolic effect of OxLDL on the vessel wall and mechanism of atherogenesis.

Key Words: reactive oxygen species • low-density lipoprotein • energy metabolism • vascular smooth muscle

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