Paraoxonases (PON), a family of orphan enzymes with multiple enzyme activities assigned to them, comprise of three proteins PON1, PON2, and PON3. The aryl esterase, organophosphatase, and lipo-lactonase activities of PON enzymes underscore their importance in inflammation, toxicology, and infection, respectively. Epidemiological studies identified PON proteins in the etiology of a number of inflammatory diseases including cardiovascular diseases. Sequence analysis of PON genes suggest that the PON family evolved by gene duplication with PON2 being the first and PON1 the most recent member. Interestingly, PON2 and PON3 are predominantly localized to intracellular compartments while PON1 is found exclusively extracellular and associated solely with HDL particles. Our laboratory has cloned and characterized both PON2 and PON3 genes, and also developed mouse models for studying the role of PON2 and PON3 in atherosclerosis. Recent studies suggest that PON2 and PON3 are associated with mitochondria and mitochondrial associated membranes and play important roles in the modulation of mitochondrial oxidative stress. PON2 protects against the development of atherosclerosis and insulin resistance. Moreover, macrophage PON2 plays a critical role in the mechanisms that mediate both the development of atherosclerosis and insulin resistance. PON3 protects against the development of atherosclerosis and obesity. Despite the role of PON2 and PON3 in critical cellular functions and associated pathologies, the physiological substrates and molecular mechanisms by which PON2 and PON3 function as anti-atherogenic and anti-inflammatory proteins are largely unknown. In this application, we propose to i. delineate the physiological substrates for PON2 and PON3 proteins, ii. determine the molecular mechanisms by which PON2 and PON3 function, and iii. to examine the role of PON2 and PON3 proteins in vascular inflammatory diseases including diabetes, obesity, and ischemic heart disease. These studies will help identify novel molecular targets for the treatment of inflammatory diseases

Public Health Relevance

PON2 and PON3 proteins play important roles in a number of vascular and inflammatory diseases. Based on recent discoveries in our laboratory, we propose experimental strategies that will allow us to, for the first time, identify the physiological substrates and determine the mechanisms by which PON2 and PON3 proteins function. Successful completion of these studies will identify novel therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
4R01HL071776-12
Application #
9066747
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Hasan, Ahmed AK
Project Start
2003-01-01
Project End
2018-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
12
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Devarajan, Asokan; Su, Feng; Grijalva, Victor et al. (2018) Paraoxonase 2 overexpression inhibits tumor development in a mouse model of ovarian cancer. Cell Death Dis 9:392
Singh, Rajan; Pervin, Shehla; Lee, Se-Jin et al. (2018) Metabolic profiling of follistatin overexpression: a novel therapeutic strategy for metabolic diseases. Diabetes Metab Syndr Obes 11:65-84
Charles-Schoeman, C; Gugiu, G B; Ge, H et al. (2018) Remodeling of the HDL proteome with treatment response to abatacept or adalimumab in the AMPLE trial of patients with rheumatoid arthritis. Atherosclerosis 275:107-114
Li, Wei; Kennedy, David; Shao, Zhili et al. (2018) Paraoxonase 2 prevents the development of heart failure. Free Radic Biol Med 121:117-126
Meriwether, David; Sulaiman, Dawoud; Wagner, Alan et al. (2016) Transintestinal transport of the anti-inflammatory drug 4F and the modulation of transintestinal cholesterol efflux. J Lipid Res 57:1175-93
Mehta, Niyati U; Grijalva, Victor; Hama, Susan et al. (2016) Apolipoprotein E-/- Mice Lacking Hemopexin Develop Increased Atherosclerosis via Mechanisms That Include Oxidative Stress and Altered Macrophage Function. Arterioscler Thromb Vasc Biol 36:1152-63
Mehta, Niyati U; Reddy, Srinivasa T (2015) Role of hemoglobin/heme scavenger protein hemopexin in atherosclerosis and inflammatory diseases. Curr Opin Lipidol 26:384-7
Shih, Diana M; Yu, Janet M; Vergnes, Laurent et al. (2015) PON3 knockout mice are susceptible to obesity, gallstone formation, and atherosclerosis. FASEB J 29:1185-97
Braga, Melissa; Reddy, Srinivasa T; Vergnes, Laurent et al. (2014) Follistatin promotes adipocyte differentiation, browning, and energy metabolism. J Lipid Res 55:375-84
Devarajan, Asokan; Shih, Diana; Reddy, Srinivasa T (2014) Inflammation, infection, cancer and all that…the role of paraoxonases. Adv Exp Med Biol 824:33-41

Showing the most recent 10 out of 32 publications