Oxidative stress is implicated in atherogenesis and plaque rupture-the major cause of myocardial infarction (MI) and sudden death. One of the well-characterized sources of oxidative stress is myeloperoxidase (MPO), a heme enzyme that co-localizes with macrophages in human atherosclerotic lesions. Epidemiology studies show that individuals possessing high MPO levels among sequential subjects undergoing diagnostic cardiac catheterization were 15- to 20-fold more likely to demonstrate abnormal coronary angiograms compared with subjects in the lowest quartile. Consistently, individuals with total or subtotal MPO deficiency appear less likely to have CVD development. Importantly, MPO selectively modifies apolipoprotein A-1 (ApoA-I), generating dysfunctional HDL. Here we hypothesize that inhibiting MPO is beneficial to the quality of HDL, which consequently exert atheroprotective effects on the patients. We propose experiments to determine whether MPO is an effective target for reducing atherosclerosis, and to define the roles of MPO on HDL functionality in atherogenesis. We have successfully generated MPO knockout (KO) rabbits using the CRISPR/Cas9 technology. These novel rabbit models will be employed in the present study. We expect establishing a meaningful animal model for the study of MPO biology, gaining novel knowledge, and facilitating the R&D of MPO based therapeutics and diagnostics. Specifically, we will 1) Determine whether MPO is an effective target for reducing atherosclerosis in rabbits; 2) Define the roles of MPO on HDL functionality in atherogenesis using novel rabbit models. It is well documented that mice are not appropriate for the study of MPO biology. Only trace amount of MPO can be detected in atherosclerotic tissues in mice, dwarf to that found in human counterpart. Moreover, mice deficient of MPO showed increased atherosclerosis, opposite to what is observed in humans. This project thus has a unique advantage in resolving such debate (i.e. MPO be atherogenic or anti-atherogenic) by using the novel MPO knockout rabbit models, a species that has been a classic model to study human lipid biology and CVD.

Public Health Relevance

Inhibiting myeloperoxidase (MPO) is an attractive therapeutic strategy of atherosclerosis. We propose to use novel MPO knockout (KO) rabbits to determine if MPO is an effective drug target, and to define the roles of MPO on HDL functionality in atherogenesis in these rabbits.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL129778-03
Application #
9265931
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Liu, Lijuan
Project Start
2015-07-01
Project End
2019-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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