Oxidation hypothesis has generated an overwhelming interest in how it might affect the atherogenic process. Despite the plethora of pro-atherogenic effects of oxidative stress, several major problems plague the hypothesis. These include, cellular defense to oxidative stress, prooxidant nature of exercise, PUFA, and estrogens, and the rapid clearance of oxidized LDL from plasma. There is an a priori need to amend the hypothesis to include these factors. Based on findings in literature and our preliminary results, we propose that """"""""oxidative stress in plasma might result in an elevated tissue (arterial) antioxidant enzyme induction and, in addition, such oxidative stress might itself could lead to lower plasma cholesterol levels."""""""" In other words, an oxidative stress might help to maintain a high level of antioxidant protection in tissues and combined with the lowering of plasma cholesterol, would help to attenuate the atherogenic process. We propose the following specific aims: 1. To demonstrate that oxidative stress would lead to elevated tissue antioxidant defense and decrease atherosclerosis. 2. To demonstrate that oxidative stress might lead to decreased LDL cholesterol levels via an enhanced clearance of oxidized lipoproteins or via decreased de novo liver cholesterol synthesis mediated by cholesterol oxidation products. 3. To demonstrate that antioxidant supplementation during the """"""""beneficial oxidative stress acclimatization period"""""""" would be counter productive and reduce the beneficial effects of plasma oxidative stress. 4. To determine the effects of exercise-induced oxidative stress on the regression of atherosclerotic lesions in LDL r -/- mice. Since fatty streak lesion starts early in life, the study would suggest that the consumption of PUFA rich diet and exercise from childhood would ensure adequate antioxidant defense and protection from atherosclerosis. Exercise is also recommended for other diseases such as diabetes and hypertension, diseases in which oxidative stress is also implicated. Thus the outcome of this study will have far reaching implications.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL069038-02
Application #
6620758
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Wassef, Momtaz K
Project Start
2001-12-01
Project End
2006-11-30
Budget Start
2002-12-01
Budget End
2003-11-30
Support Year
2
Fiscal Year
2003
Total Cost
$380,000
Indirect Cost
Name
Emory University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Garelnabi, M; Veledar, E; White-Welkley, J et al. (2012) Vitamin E differentially affects short term exercise induced changes in oxidative stress, lipids, and inflammatory markers. Nutr Metab Cardiovasc Dis 22:907-13
Penumetcha, M; Song, M; Merchant, N et al. (2012) Pretreatment with n-6 PUFA protects against subsequent high fat diet induced atherosclerosis--potential role of oxidative stress-induced antioxidant defense. Atherosclerosis 220:53-8
Jiang, Xueting; Yang, Zhaohui; Chandrakala, Aluganti Narasimhulu et al. (2011) Oxidized low density lipoproteins--do we know enough about them? Cardiovasc Drugs Ther 25:367-77
Garelnabi, Mahdi; Veledar, Emir; Abramson, Jerome et al. (2010) Physical inactivity and cardiovascular risk: baseline observations from men and premenopausal women. J Clin Lab Anal 24:100-5
Litvinov, Dmitry; Selvarajan, Krithika; Garelnabi, Mahdi et al. (2010) Anti-atherosclerotic actions of azelaic acid, an end product of linoleic acid peroxidation, in mice. Atherosclerosis 209:449-54
Parthasarathy, Sampath; Raghavamenon, Achuthan; Garelnabi, Mahdi Omar et al. (2010) Oxidized low-density lipoprotein. Methods Mol Biol 610:403-17
Raghavamenon, Achuthan; Garelnabi, Mahdi; Babu, Sainath et al. (2009) Alpha-tocopherol is ineffective in preventing the decomposition of preformed lipid peroxides and may promote the accumulation of toxic aldehydes: a potential explanation for the failure of antioxidants to affect human atherosclerosis. Antioxid Redox Signal 11:1237-48
Garelnabi, Mahdi; Selvarajan, Krithika; Litvinov, Dmitry et al. (2008) Dietary oxidized linoleic acid lowers triglycerides via APOA5/APOClll dependent mechanisms. Atherosclerosis 199:304-9
Jaichander, Priscilla; Selvarajan, Krithika; Garelnabi, Mahdi et al. (2008) Induction of paraoxonase 1 and apolipoprotein A-I gene expression by aspirin. J Lipid Res 49:2142-8
Parthasarathy, Sampath; Litvinov, Dmitry; Selvarajan, Krithika et al. (2008) Lipid peroxidation and decomposition--conflicting roles in plaque vulnerability and stability. Biochim Biophys Acta 1781:221-31

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