Published online before print October 30, 2003, doi: 10.1161/01.RES.0000104087.29395.66
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© 2003 American Heart Association, Inc.
Molecular Medicine |
Pulsatile Versus Oscillatory Shear Stress Regulates NADPH Oxidase Subunit Expression
Implication for Native LDL Oxidation
From the Department of Biomedical Engineering and Division of Cardiovascular Medicine (J.H., M.H.I., A.S., T.K.H.) and Department of Molecular Pharmacology and Toxicology (J.H., A.S.), University of Southern California, Los Angeles, Calif; Division of Cardiology (B.L., K.G.), Emory University, Atlanta, Ga; and Division of Cardiology, Department of Medicine (M.N.), University of California Los Angeles, Calif.
Correspondence to T.K. Hsiai, MD, PhD, Department of Biomedical Engineering and Division of Cardiovascular Medicine, University of Southern California, Los Angeles, CA. E-mail hsiai{at}usc.edu
Shear stress regulates endothelial nitric oxide and superoxide (O2-·) production, implicating the role of NADPH oxidase activity. It is unknown whether shear stress regulates the sources of reactive species production, consequent low-density lipoprotein (LDL) modification, and initiation of inflammatory events. Bovine aortic endothelial cells (BAECs) in the presence of 50 µg/mL of native LDL were exposed to (1) pulsatile flow with a mean shear stress (
ave) of 25 dyne/cm2 and (2) oscillating flow at ave of 0. After 4 hours, aliquots of culture medium were collected for high-performance liquid chromatography analyses of electronegative LDL species, described as LDL- and LDL2-. In response to oscillatory shear stress, gp91phox mRNA expression was upregulated by 2.9±0.3-fold, and its homologue, Nox4, by 3.9±0.9-fold (P<0.05, n=4), with a corresponding increase in O2-· production rate. The proportion of LDL- and LDL2- relative to static conditions increased by 67±17% and 30±7%, respectively, with the concomitant upregulation of monocyte chemoattractant protein-1 expression and increase in monocyte/BAEC binding (P<0.05, n=5). In contrast, pulsatile flow downregulated both gp91phox and Nox4 mRNA expression (by 1.8±0.2-fold and 3.0±0.12-fold, respectively), with an accompanying reduction in O2-· production, reduction in the extent of LDL modification (51±12% for LDL- and 30±7% for LDL2-), and monocyte/BAEC binding. The flow-dependent LDL oxidation is determined in part by the NADPH oxidase activity. The formation of modified LDL via O2-· production may also affect the regulation of monocyte chemoattractant protein-1 expression and monocyte/BAEC binding.
Key Words: shear stress • NADPH oxidase • LDL oxidation • Nox4 • gp91phox
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