Abstract 14073: The Nucleophilic Dipeptide Carnosine Prevents Atherogenesis in ApoE-Null Mice
Atherogenesis is associated with the accumulation of oxidized lipids within atherosclerotic lesions. Among those, aldehydes generated from fragmentation of unsaturated fatty acids are the major, and some of the most toxic, end-products. These aldehydes form covalent adducts with lipoproteins, leading to their uptake by the scavenger receptors and resulting in the formation of foam cells. Recently, we have shown that inhibition of aldehyde metabolism exacerbates atherosclerosis and enhances the accumulation of aldehyde-modified proteins in atherosclerotic plaques. However, therapeutic interventions for decreasing atherogenesis by preventing aldehyde toxicity have not been devised. In the present study we examined the effect of carnosine (a naturally occurring beta-alanyl-histidine dipeptide) on aldehyde quenching and atherogenesis. In vitro, carnosine reacted rapidly with oxidized lipids -derived unsaturated aldehydes - acrolein, 4-hydroxynonenal (HNE) and 4-oxononenal with bimolecular rate constants of 0.51, 0.048, and 0.034 M-1s-1, respectively. Gas chromatography mass spectrometry analysis showed that carnosine also inhibited the formation of free aldehydes - HNE and malonaldialdehyde in Cu2+-oxidized LDL by 5-fold. Preloading of murine bone marrow derived macrophages (BMDM) with cell-permeable carnosine analogs reduced HNE-induced apoptosis by 45%. Carnosine also inhibited HNE and tunicamicin-induced endoplasmic reticulum (ER) stress in BMDM. Oral supplementation with octyl-D-carnosine (60 mg/kg/day) for 6 weeks to 8-week-old female apoE−/− mice (n=12) maintained on high fat diet, decreased lesion formation in the aortic valves by 25 % (P<0.05). Carnosine feeding also attenuated the accumulation of protein-HNE and protein-acrolein adducts and ER-stress responsive pro-inflammatory protein activating transcription factor 3 in atherosclerotic lesions and increased the excretion of corresponding carnosine-aldehyde conjugates in urine. Together, our data suggest that carnosine inhibits atherogenesis by facilitating aldehyde removal and inhibiting ER-stress. Aldehyde quenchers such as carnosine could therefore be potential therapies for the prevention and treatment of atherosclerosis and inflammation.
- © 2011 by American Heart Association, Inc.