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.
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.
