Recent breakthroughs in our understanding of pathobiology of atherogenesis necessitate revision of overly simplistic concept of 'good and bad cholesterol and suggest novel directions for the development of effective therapies. During the last few years, oxidation of low density lipoproteins (LDL) and scavenger-receptor dependent internalization of oxidized LDL (ox-LDL) by vascular cells was established to be a main factor driving atherogenesis. Endothelial monolayer is a primary component of vascular wall interacting with oxidatively modified LDL. Its activation and angiogenic responses are prerequisites for initiation and progression of atherosclerosis as well as plaque instability and eventual rupture. Our group has shown that ox-LDL internalization is mediated predominantly by a lectin-like ox-LDL receptor (LOX-1) and that ox-LDL mediated stimulation of angiogenesis is LOX-1 dependent. In our earlier studies in a murine model of hypercholesterolemia, we have also shown that abrogation of LOX-1 results in significant attenuation of atherosclerosis. Based on these findings we believe that LOX-1 may become an attractive target for therapeutic interventions. In search for approaches to inhibition of ox-LDL/endothelium interactions, we have determined microRNAs implicated in LOX-1 regulation and ox-LDL downstream signaling using physiologically realistic exposures to ox-LDL. We have also screened and identified candidate small molecules that, based on existing models of LOX-1/ox- LDL interactions, demonstrate a potential to block LOX-1 binding site. We propose to conduct studies that would evaluate miRNA and small molecules based therapies with regard to plaque angiogenesis and progression of atherosclerosis. The objectives of the current proposal are to: a) further elucidate the role of ox- LDL/LOX-1 signaling in relation to angiogenesis, and b) determine efficacy of LOX-1- centered miRNA and small molecule-based interventions in prevention of angiogenesis and atherosclerosis. The PI has been engaged in the research on LOX-1 biology for the last 15 years and his group significantly contributed to elucidation of LOX-1 biology - especially in relation to cardiovascular conditions - with more than 50 publications in major peer- reviewed journals.

Public Health Relevance

Atherosclerosis is a main cause of death in the United States. One of the mechanisms responsible for development and growth of atherosclerotic plaque as well as its instability and eventual rupture is formation of new blood vessels within the plaque (angiogenesis). This process to a large degree depends on scavenger receptor LOX-1 mediated internalization of oxidized LDL by endothelial cells. We propose to develop new ways of treatment of atherosclerosis by using microRNAs (micro-ribonucleic acids that occur naturally in our bodies) and small molecules to block LOX-1 and prevent angiogenesis. We believe that our studies will lead to novel and highly effective methods for preventing many cardiovascular diseases including heart attack and stroke.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX000282-08
Application #
9275306
Study Section
Cardiovascular Studies A (CARA)
Project Start
2009-04-09
Project End
2017-09-30
Budget Start
2016-10-01
Budget End
2017-09-30
Support Year
8
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Central Arkansas Veterans Hlthcare Sys
Department
Type
Independent Hospitals
DUNS #
082573742
City
North Little Rock
State
AR
Country
United States
Zip Code
72114
Wang, Xian-Wei; Zhang, Fen-Xi; Yang, Fen et al. (2016) Effects of linagliptin and liraglutide on glucose- and angiotensin II-induced collagen formation and cytoskeleton degradation in cardiac fibroblasts in vitro. Acta Pharmacol Sin 37:1349-1358
Ayyadevara, Srinivas; Mercanti, Federico; Wang, Xianwei et al. (2016) Age- and Hypertension-Associated Protein Aggregates in Mouse Heart Have Similar Proteomic Profiles. Hypertension 67:1006-13
Ding, Zufeng; Liu, Shijie; Deng, Xiaoyan et al. (2015) Hemodynamic shear stress modulates endothelial cell autophagy: Role of LOX-1. Int J Cardiol 184:86-95
Ding, Zufeng; Liu, Shijie; Wang, Xianwei et al. (2015) Hemodynamic shear stress via ROS modulates PCSK9 expression in human vascular endothelial and smooth muscle cells and along the mouse aorta. Antioxid Redox Signal 22:760-71
Wang, Xianwei; Guo, Zhikun; Ding, Zufeng et al. (2015) Endothelin-1 upregulation mediates aging-related cardiac fibrosis. J Mol Cell Cardiol 80:101-9
Ding, Zufeng; Liu, Shijie; Wang, Xianwei et al. (2015) Lectin-like oxidized low-density lipoprotein receptor-1 regulates autophagy and Toll-like receptor 4 in the brain of hypertensive mice. J Hypertens 33:525-33; discussion 533
Mehta, Jawahar L; Mercanti, Federico; Stone, Annjannette et al. (2015) Gene and microRNA transcriptional signatures of angiotensin II in endothelial cells. J Cardiovasc Pharmacol 65:123-9
Ding, Zufeng; Liu, Shijie; Wang, Xianwei et al. (2015) Lectin-like ox-LDL receptor-1 (LOX-1)-Toll-like receptor 4 (TLR4) interaction and autophagy in CATH.a differentiated cells exposed to angiotensin II. Mol Neurobiol 51:623-32
Ding, Zufeng; Liu, Shijie; Wang, Xianwei et al. (2015) Cross-talk between LOX-1 and PCSK9 in vascular tissues. Cardiovasc Res 107:556-67
Mathur, Pankaj; Ding, Zufeng; Saldeen, Tom et al. (2015) Tocopherols in the Prevention and Treatment of Atherosclerosis and Related Cardiovascular Disease. Clin Cardiol 38:570-6

Showing the most recent 10 out of 24 publications