Atherosclerosis is a systemic disease;however, its manifestations tend to be focal and eccentric. Hemodynamics, specifically, fluid shear stress, is intimately involved in vascular oxidative stress. Oxidative stress induces molecular signaling regulates the development of intimal calcification that has been identified as a distinct, but relevant process to atherosclerosis. The vascular cells that calcify, previously termed calcifying vascular cells (CVC), are multipotent, with the capacity for chondrogenic, leiomyogenic (smooth muscle), and stromogenic (marrow stromal) lineages. Whether vascular calcification stabilizes atherosclerotic plaques or promotes plaque rupture remains undefined. We propose to assess vascular oxidative stress in non-obstructive, albeit inflammatory, lesions in explants of human coronary arteries and New Zealand White (NZW) rabbits. The development of Micro Electro Mechanical Systems (MEMS) shear stress and oxidative stress sensors in our lab has provided a means to undertake study of atherogenic hemodynamics and vascular oxidative stress. We hypothesize that flow disturbance as assessed by the micro-scale sensors in non-obstructive plaques is associated with oxidative stress relevant for initiation of the arterial plaque. This hypothesis will be tested by three Aims:
Aim 1 : Assess vascular oxidative stress in arterial regions exposed to atherogenic hemodynamics. The level of vascular oxidative stress will be determined from explants of arterial bifurcations of human coronary arteries using the MEMS oxidative stress sensors. Immunohistochemistry will validate oxidative content, including oxidized low density lipoprotein (oxLDL), foam cells and intimal calcification, in the regions exposed to atherogenic hemodynamics.
Aim 2 : Determine shear stress and oxidative stress in non-obstructive plaque. Intravascular sensors will be deployed into the aortas of NZW rabbits. Athero-prone regions will be localized by shear stress sensors and vascular oxidative stress will be assessed prior to and after hypercholesterolemic diet. The rabbit aorta will be dissected for immuno-staining for regions that harbor oxidative stress.
Aim 3 : Study whether vascular calcification stabilizes a mechanically unstable plaque. Vascular mesenchymal stem cell (MSC)-derived plaque that harbors oxLDL, foam cells, and calcification will be used in an in vitro model. Atherogenic hemodynamics;namely, low and oscillatory shear stress, will be delivered and plaque rupture will be captured in the context of vascular oxidative stress and calcification. Our proposal represents a concerted effort between two labs (Tzung Hsiai and Linda Demer) to test hypothesis, to establish causality, and to assess mechanically unstable plaque in the presence of calcification. Our research is relevant to public health because a better understanding of the biomechanics of rupture-prone plaques has the potential to reduce the morbidity and mortality associated with atherothrombotic disease.

Public Health Relevance

This research is relevant to public health because a better understanding of the biomechanics of rupture-prone plaques has the potential to reduce the morbidity and mortality associated with atherothrombotic disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL091302-02
Application #
7849610
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Fleg, Jerome
Project Start
2009-07-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2012-06-30
Support Year
2
Fiscal Year
2010
Total Cost
$193,704
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
Lee, Juhyun; Packard, René R Sevag; Hsiai, Tzung K (2015) Blood flow modulation of vascular dynamics. Curr Opin Lipidol 26:376-83
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Zhang, Xiaoxiao; Beebe, Tyler; Jen, Nelon et al. (2015) Flexible and waterproof micro-sensors to uncover zebrafish circadian rhythms: The next generation of cardiac monitoring for drug screening. Biosens Bioelectron 71:150-157
Cao, Hung; Yu, Fei; Zhao, Yu et al. (2014) Stretchable electrochemical impedance sensors for intravascular detection of lipid-rich lesions in New Zealand White rabbits. Biosens Bioelectron 54:610-6
Yu, Fei; Lee, Juhyun; Jen, Nelson et al. (2013) Elevated electrochemical impedance in the endoluminal regions with high shear stress: implication for assessing lipid-rich atherosclerotic lesions. Biosens Bioelectron 43:237-44
Jen, Nelson; Yu, Fei; Lee, Juhyun et al. (2013) Atrial fibrillation pacing decreases intravascular shear stress in a New Zealand white rabbit model: implications in endothelial function. Biomech Model Mechanobiol 12:735-45
Li, Rongsong; Navab, Mohamad; Pakbin, Payam et al. (2013) Ambient ultrafine particles alter lipid metabolism and HDL anti-oxidant capacity in LDLR-null mice. J Lipid Res 54:1608-15
Li, Rongsong; Mittelstein, David; Kam, Winnie et al. (2013) Atmospheric ultrafine particles promote vascular calcification via the NF-?B signaling pathway. Am J Physiol Cell Physiol 304:C362-9
Li, Rongsong; Mittelstein, David; Fang, Karen et al. (2012) Angiopoeitin-2 modulates Survivin expression in OxLDL-induced endothelial cell apoptosis. Biochem Biophys Res Commun 417:619-22
Li, Rongsong; Mittelstein, David; Lee, Juhyun et al. (2012) A dynamic model of calcific nodule destabilization in response to monocyte- and oxidized lipid-induced matrix metalloproteinases. Am J Physiol Cell Physiol 302:C658-65

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