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

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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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
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Hasan, Ahmed AK
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University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
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Gao, Feng; Liang, Bin; Reddy, Srinivasa T et al. (2014) Role of inflammation-associated microenvironment in tumorigenesis and metastasis. Curr Cancer Drug Targets 14:30-45
Braga, Melissa; Reddy, Srinivasa T; Vergnes, Laurent et al. (2014) Follistatin promotes adipocyte differentiation, browning, and energy metabolism. J Lipid Res 55:375-84
Sharma, Salil; Umar, Soban; Potus, Francois et al. (2014) Apolipoprotein A-I mimetic peptide 4F rescues pulmonary hypertension by inducing microRNA-193-3p. Circulation 130:776-85
Parsanejad, Mohammad; Bourquard, Noam; Qu, Dianbo et al. (2014) DJ-1 interacts with and regulates paraoxonase-2, an enzyme critical for neuronal survival in response to oxidative stress. PLoS One 9:e106601
Devarajan, Asokan; Bourquard, Noam; Grijalva, Victor R et al. (2013) Role of PON2 in innate immune response in an acute infection model. Mol Genet Metab 110:362-70
Bourquard, Noam; Ng, Carey J; Reddy, Srinivasa T (2011) Impaired hepatic insulin signalling in PON2-deficient mice: a novel role for the PON2/apoE axis on the macrophage inflammatory response. Biochem J 436:91-100
Kim, Juyong Brian; Xia, Yu-Rong; Romanoski, Casey E et al. (2011) Paraoxonase-2 modulates stress response of endothelial cells to oxidized phospholipids and a bacterial quorum-sensing molecule. Arterioscler Thromb Vasc Biol 31:2624-33
Shih, Diana M; Lusis, Aldons J (2009) The roles of PON1 and PON2 in cardiovascular disease and innate immunity. Curr Opin Lipidol 20:288-92
Reddy, Srinivasa T; Devarajan, Asokan; Bourquard, Noam et al. (2008) Is it just paraoxonase 1 or are other members of the paraoxonase gene family implicated in atherosclerosis? Curr Opin Lipidol 19:405-8
Lin, James A; Watanabe, Junji; Rozengurt, Nora et al. (2007) Atherogenic diet causes lethal ileo-ceco-colitis in cyclooxygenase-2 deficient mice. Prostaglandins Other Lipid Mediat 84:98-107

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