Metabolic disorders including obesity, dyslipidemia and diabetes appear to be associated with monocyte dysfunction, yet the molecular mechanisms underlying monocyte dysfunction in vivo are only poorly understood. Our recent studies showed that metabolic stress promotes the dysregulation and hyper-activation of monocyte responses to chemokines and that monocyte dysfunction is a critical and rate-limiting step in the development and progression of atherosclerosis. We have now found that dietary supplementation with ursolic acid, a triterpenoid with anti-inflammatory properties, attenuate monocyte dysfunction and macrophage recruitment and protects diabetic mice from atherosclerosis. In addition, we have elucidated key steps in a novel mechanism through which hypercholesterolemia and hyperglycemia promote monocyte dysfunction, and have identified several novel potential targets for the anti-atherogenic and anti-inflammatory activity of ursolic acid and its analogues. Based on these data, we hypothesize that ursolic acid protects against monocyte dysfunction and atherosclerosis by preventing metabolic stress-induced protein-S-glutathionylation, inactivation and degradation of mitogen-activated protein kinase phosphatases (MKP) in monocytes. To test our hypothesis and to identify both the structural features of ursolic acid responsible for the anti- atherogenic properties and the molecular mechanisms involved in monocyte protection, we propose two Specific Aims:
Specific Aim 1 : To determine the protective mechanisms through which ursolic acid and its analogues prevent monocyte dysfunction induced by metabolic stress.
Specific Aim 2 : To determine the mechanism by which dietary ursolic acid and its analogues protect against atherosclerosis. The goal of this application is to identify the atheroprotective mechanism(s) of ursolic acid and structurally related phytochemicals.

Public Health Relevance

Our data suggest that monocyte dysfunction is a critical and rate-limiting step in the development and progression of atherosclerosis, yet the molecular mechanisms underlying monocyte dysfunction are still unclear. We recently found that supplementation of the diet with ursolic acid, a triterpenoid with anti- inflammatory properties, protected monocytes from dysfunction, attenuated macrophage recruitment and protected diabetic mice from atherosclerosis. This application aims to identify both the structural features of ursolic acid responsible for the anti-atherogenic properties and the molecular mechanisms involved in monocyte protection.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Research Project (R01)
Project #
1R01AT006885-01A1
Application #
8444366
Study Section
Special Emphasis Panel (ZAT1-SM (27))
Program Officer
Alekel, D Lee
Project Start
2013-01-01
Project End
2017-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
1
Fiscal Year
2013
Total Cost
$361,228
Indirect Cost
$111,228
Name
University of Texas Health Science Center San Antonio
Department
Other Health Professions
Type
Schools of Allied Health Profes
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Ullevig, Sarah L; Kim, Hong Seok; Nguyen, Huynh Nga et al. (2014) Ursolic acid protects monocytes against metabolic stress-induced priming and dysfunction by preventing the induction of Nox4. Redox Biol 2:259-66