Accumulation of oxidized low density lipoproteins (OxLDL) in the intima of arteries causes atherosclerosis. In contrast, HDL protects against atherosclerosis via its enzyme paraoxonase (PON) that destroys OxLDL. Whereas moderate wine consumption is cardioprotective, the benefits of both ethanol and quercetin components of wine on herogenic/antiatherogenic (AAA) factors are not clearly defined. A major advancement and clinically relevant new approach would be to directly correlate the possible beneficial effects of quercetin and/or ethanol on AAA factors (PON status, HDL's capacity to inhibit LDL oxidation, LDL particle size, and OxLDL level in aorta) with the extent of atherosclerosis in the aorta (morphometric analysis of aorta) in an animal model. Such a direct correlation is difficult in a prospective human trial. LDLR-/- mouse is an excellent model that promptly develops atherosclerosis on a cholesterol cholatecontaining diet. This enables a systematic evaluation of the effects of alcohol/quercetin not only on AAA factors, but also on the extent of atherosclerosis as a function of time. PI has the following preliminary data in support of this proposal: 1. Serum and liver PON activity and liver PON mRNA level were significantly up egulated in LDLR-/- mice fed quercetin for 8 weeks compared to the controls. 2. HDLs from quercetin-fed LDLR-/- mice were more protective against LDL oxidation (this was shown to be due to HDL's PON component) compared to the HDLs from controls. 4. Feeding atherogenic diet for 8 weeks markedly decreased serum and liver PON activity and liver PON mRNA level coupled with extensive aortic plaques in LDL-/- mice. 5. Moderate alcohol feeding for 8 weeks: increased serum & liver PON activity in LDLR-/- mice. PI has these specific aims to delineate the action of alcohol/quercetin on AAA factors and atherosclerosis:
Aim 1. Optimal dietary concentration.
Aim 2. Optimal time of feeding.
Aim 3. Possible Mechanism/s of Action.
Aim 4. Effects on antioxidant Property of HDLs. The data will be statistically analyzed using SAS software. Thus, this exploratory study would logically lead to a well-controlled human trial to conclusively prove the possible independent benefits of moderate alcohol/quercetin in cardioprotection via the regulation of AAA factors. Therefore, this mechanistic and clinically releyent study on the actions of alcohol/quercetin has the potential to effectively protect against cardiovascular diseases. ? ? ?
| Leckey, Leslie C; Garige, Mamatha; Varatharajalu, Ravi et al. (2010) Quercetin and ethanol attenuate the progression of atherosclerotic plaques with concomitant up regulation of paraoxonase1 (PON1) gene expression and PON1 activity in LDLR-/- mice. Alcohol Clin Exp Res 34:1535-42 |
| Varatharajalu, Ravi; Garige, Mamatha; Leckey, Leslie C et al. (2010) Betaine protects chronic alcohol and omega-3 PUFA-mediated down-regulations of PON1 gene, serum PON1 and homocysteine thiolactonase activities with restoration of liver GSH. Alcohol Clin Exp Res 34:424-31 |
