Fluid shear stress imparts both metabolic and mechanical effects on vascular endothelial function. The spatial ( D/ x) and temporal ( D/ t) components of shear stress largely determine the focal nature of vascular oxidative stress, leading to pro-inflammatory states. The focus of the previous grant period was a paradigm shift in the approach from one of the static models (oxidative biology) to the dynamic models of investigation (vascular oxidative stress) that combined biophysical and biochemical approaches of pathophysiological significance. We demonstrated that variations in D/ x and D/ t differentially regulated the endothelial production of O2.- and .NO, leading to low density lipoprotein (LDL) oxidative modifications relevant for the initiation of atherosclerotic lesions. We developed microelectromechanical systems (MEMS) sensors to measure in real-time intravascular shear stress in the New Zealand White (NZW) rabbits on a hypercholesterolemic diet, and applied our intravascular methodology to the swine model. We gained new insights into the mechanisms whereby atheroprotective hemodynamics increased mitochondrial membrane potential ( (m) accompanied by a decrease in mitochondrial O2.- production via an up-regulation in Mn-SOD activities. In contrast, atherogenic hemodynamics and oxidized LDL induced mitochondrial O2.- production, leading to apoptosis via c-Jun NH2 terminal kinase (JNK)-induced Mn-SOD ubiquitination and protein degradation. Our finding led to a novel observation that active lipid and macrophages in the vessel wall cause electrochemical modifications that can be measured by electrochemical impedance spectroscopy (EIS). In this context, we hypothesize that shear stress regulates mitochondrial redox status, modulating vascular oxidative stress to cause distinct changes in electrochemical impedance in regions of non-obstructive, albeit inflammatory lesions. In the new Aim 1, we will provide an ex vivo model of EIS;specifically, the frequency-dependent electrical and dielectrical properties between concentric bipolar microelectrodes and endoluminal surface of explants of human arteries and NZW rabbit aortas.
In Aim 2, we will establish an in vivo model of EIS measurements using fat-fed NZW rabbits;specifically, microfabrication and deployment of the electrodes for intravascular EIS measurements.
In Aim 3, we will provide molecular and genetic models to demonstrate redox signaling as a requite factor underlying changes in electrochemical modifications. The focus in the next grant period will integrate electrochemical, redox signaling, and genetic approaches to establish specific EIS that occur in response to local pro- inflammatory states during angiograms with the possibility of identifying unstable plaque. In summary, the publication record (30 corresponding authors) of our laboratory in the previous funding cycle is a testimony of our commitment and productivity in mechanobiology and vascular oxidative stress research.

Public Health Relevance

Atherosclerosis is a systemic disease;however, its manifestations tend to be focal and eccentric. We have developed an electrochemical approach to assess LDL oxidation and foam cells in the vessel wall as quantified by electrochemical impedance spectroscopy (EIS). The focus for the next cycle will integrate electrochemical, redox signaling, and genetic approaches to establish specific EIS that occur in response to local pro- inflammatory states with the possibility of identifying unstable plaque when patients undergo angiograms.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL083015-06
Application #
8109140
Study Section
Special Emphasis Panel (ZRG1-SBIB-E (02))
Program Officer
Liu, Lijuan
Project Start
2006-01-01
Project End
2016-05-31
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
6
Fiscal Year
2011
Total Cost
$399,481
Indirect Cost
Name
University of Southern California
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Ding, Yichen; Abiri, Arash; Abiri, Parinaz et al. (2017) Integrating light-sheet imaging with virtual reality to recapitulate developmental cardiac mechanics. JCI Insight 2:
Packard, René R Sevag; Luo, Yuan; Abiri, Parinaz et al. (2017) 3-D Electrochemical Impedance Spectroscopy Mapping of Arteries to Detect Metabolically Active but Angiographically Invisible Atherosclerotic Lesions. Theranostics 7:2431-2442
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Abiri, Parinaz; Abiri, Ahmad; Packard, René R Sevag et al. (2017) Inductively powered wireless pacing via a miniature pacemaker and remote stimulation control system. Sci Rep 7:6180
Packard, René R Sevag; Baek, Kyung In; Beebe, Tyler et al. (2017) Automated Segmentation of Light-Sheet Fluorescent Imaging to Characterize Experimental Doxorubicin-Induced Cardiac Injury and Repair. Sci Rep 7:8603
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Fei, Peng; Lee, Juhyun; Packard, René R Sevag et al. (2016) Cardiac Light-Sheet Fluorescent Microscopy for Multi-Scale and Rapid Imaging of Architecture and Function. Sci Rep 6:22489
Ma, Jianguo; Luo, Yuan; Sevag Packard, René R et al. (2016) Ultrasonic Transducer-Guided Electrochemical Impedance Spectroscopy to Assess Lipid-Laden Plaques. Sens Actuators B Chem 235:154-161
Lee, Juhyun; Fei, Peng; Packard, René R Sevag et al. (2016) 4-Dimensional light-sheet microscopy to elucidate shear stress modulation of cardiac trabeculation. J Clin Invest 126:1679-90
Packard, René R Sevag; Zhang, XiaoXiao; Luo, Yuan et al. (2016) Two-Point Stretchable Electrode Array for Endoluminal Electrochemical Impedance Spectroscopy Measurements of Lipid-Laden Atherosclerotic Plaques. Ann Biomed Eng 44:2695-706

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