The paraoxonase (PON) gene family consists of three family members, PON1, PON2 and PONS. PON genes are implicated in the pathogenesis of several inflammatory diseases including atherosclerosis. All three PON proteins possess antioxidant properties and lactonase activities;however, the physiological substrates for PON proteins and their mechanism of action remain unknown. Our long-term goal is to understand the role of PON2 and PONS proteins in physiology and disease. During the last grant period, we have developed transgenic/knockout mouse models for PON2 and PONS genes, and provided the first in vivo evidence for the anti-atherogenic functions of PON2 and PONS proteins. We have also demonstrated that oxidized phospholipids or lipid peroxidation products are not direct substrates for purified PON enzymes, suggesting that direct inactivation of atherogenic oxidized phospholipids is not a key mechanism of action of PON proteins. We propose that the anti-atherogenic activities of PON proteins are a result of their activity towards a class of unidentified pro-inflammatory lipo-lactones that participate in LDL oxidation. Interestingly, in a very exciting turn of events, we recently discovered that PON2 and PONS proteins degrade gram-negative bacterial density-dependent sensing molecules termed acyl homoserine lactones (AHL) involved in gram-negative virulence. AHLs are lipo-lactones. Since gram-negative virulence is well established in the pathology of inflammatory diseases, including atherosclerosis, we propose that protection against pro-inflammatory pathways mediated by gram-negative virulence factors, such as AHLs, and other unidentified pro-inflammatory lipo-lactones, is a key physiological function of PON proteins. We will test this hypothesis in PON2 and PONS transgenic/knockout mouse models under two specific aims to 1) investigate the molecular mechanisms and function of PON2 and PONS in mitigating the development of atherosclerosis and 2) determine whether PON2 and PONS play a role in host defense against pro-inflammatory quorum sensing molecules and gram-negative bacterial infection. We hypothesize that PON2 and PONS are a novel class of lactonases that degrade i) atherogenic lipo-lactones associated with atherosclerosis, and ii) pro-inflammatory acyl homoserine lactones associated with gram-negative bacteria, thus preventing the pathogenesis of inflammatory diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Hasan, Ahmed AK
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
Zip Code
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