Submitted on November 4, 2007
Accepted on April 11, 2008
Shear Stress Influences Spatial Variations in Vascular Mn-SOD Expression: Implication for LDL Nitration
Lisong Ai1, Mahsa Rouhanizadeh1, Joseph C Wu2, Wakako Takabe1, Hongyu Yu1, Mohammad Alavi3, Rongsong Li1, Yi Chu4, Jordan D Miller4, Donald D. Heistad4, and Tzung Hsiai5*
1 Biomedical Engineering, University of Southern California, Los Angeles, California, United States
2 Radiology, Stanford University Medical Center, Stanford, California, United States
3 Department of Pathology, University of Southern California, Los Angeles, California, United States
4 Department of Internal Medicine, University of Iowa, Iowa City, Iowa, United States
5 University of Southern California; Biomedical Engineering, University of Southern California, Los Angeles, California, United States; Biomedical Engineering, University of Southern California, United States
* To whom correspondence should be addressed. E-mail: hsiai{at}usc.edu.
Fluid shear stress modulates vascular production of endothelial superoxide anion (O2.) and nitric oxide (.NO). Whether the characteristics of shear stress influence the spatial variations in mitochondrial manganese superoxide dismutase (Mn-SOD) expression in vasculatures is not well-defined. We constructed a 3-D Computational Fluid Dynamics model simulating spatial variations in shear stress at the arterial bifurcation. In parallel, explants of arterial bifurcations were sectioned from the human left main coronary bifurcation and right coronary arteries for immunohisto-localization of Mn-SOD expression. We demonstrated that Mn-SOD staining was prominent in the pulsatile shear stress (PSS)-exposed and athero-protective regions, but it was nearly absent in the oscillatory shear stress (OSS)-exposed regions and lateral wall of arterial bifurcation. In cultured bovine aortic endothelial cells, PSS at mean shear stress (
ave) of 23 dyn.cm-2 up-regulated Mn-SOD mRNA expression at a higher level than did OSS at ave= 0.02 dyn.cm-2 ± 3.0 dyn.cm-2.s-1 and at 1 Hz (PSS by 11.3±0.4-fold versus OSS by 5.0±0.5-fold versus static condition. p < 0.05, n=4). By liquid chromatography and tandem mass spectrometry, it was found that PSS decreased the extent of Low Density Lipoprotein (LDL) nitration, whereas OSS increased nitration (P < 0.05, n=4). In presence of LDL, treatment with Mn-SOD siRNA increased intracellular nitrotyrosine level (p < 0.5, n=4), a finger print for nitrotyrosine formation. Our findings indicate that shear stress in the athero-prone versus athero-protective regions regulates spatial variations in mitochondrial Mn-SOD expression with an implication for modulating LDL nitration.
