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1 Davis Heart & Lung Research Institute, Internal Medicine & Biomedical Engineering, The Ohio State University, Columbus, Ohio, United States
2 Davis Heart & Lung Research Institute, Internal Medicine, The Ohio State University, Columbus, Ohio, United States
* To whom correspondence should be addressed. E-mail: Rita.Alevriadou{at}osumc.edu.
There is evidence that nitric oxide (NO), superoxide (O2·--) and their associated reactive nitrogen species (RNS) produced by vascular endothelial cells (ECs) in response to hemodynamic forces play a role in cell signaling. NO is known to impair mitochondrial respiration. We sought to determine whether exposure of human umbilical vein ECs (HUVECs) to steady laminar shear stress and the resultant NO production modulate the electron transport chain (ETC) enzymatic activities. The activities of respiratory complexes I, II/III and IV were dependent on the presence of serum and growth factor supplement in the media. EC exposure to steady laminar shear stress (10 dynes/cm2) resulted in a gradual inhibition of each of the complexes starting as early as 5 min from the flow onset and lasting up to 16 h. Ramp flow resulted in similar inhibition of the complexes as step flow. When ECs were sheared in the presence of either the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 100 µM), the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (c-PTIO; 100 µM) or the peroxynitrite (ONOO--) scavenger uric acid (UA; 50 µM), the flow inhibitory effect on mitochondrial complexes was attenuated. In particular, L-NAME and UA abolished the flow effect on complex IV. Increased tyrosine nitration was observed in the mitochondria of sheared ECs, and UA blocked the shear-induced nitrotyrosine staining. In summary, shear stress induces mitochondrial RNS formation that inhibits the electron flux of the ETC at multiple sites. This may be a critical mechanism by which shear stress modulates EC signaling and function.
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