D-carnosine-octylester attenuates atherosclerosis and renal disease in ApoE null mice fed a Western diet through reduction of carbonyl stress and inflammation

Background and purpose.  Lipoxidation-derived reactive carbonyl species (RCS) such as 4-hydroxy-2-nonenal (HNE) react with proteins to form advanced lipoxidation endproducts (ALEs), which have been implicated in both atherosclerosis and renal disease. L-carnosine (CAR) was shown to act as an endogenous HNE scavenger, but it is rapidly inactivated by carnosinase. This study aimed at assessing the effect of the carnosinase-resistant D-CAR on HNE-induced cellular injury and of its bioavailable pro-drug D-CAR-octylester on experimental atherosclerosis and renal disease. Experimental approach.  Vascular smooth muscle cells (VSMCs) were exposed to HNE or H(2) O(2) plus D-CAR, whereas ApoE null mice fed a Western, pro-atherogenic diet were treated with D-CAR-octylester for 12 weeks. Key results.  In vitro, D-CAR attenuated the effect of HNE, but not of H(2) O(2) ,on VSMCs. In vivo, D-CAR-octylester-treated mice showed significantly reduced lesion area and a more stable plaque phenotype compared with untreated animals, with reduced foam cell accumulation, inflammation and apoptosis and increased clearance of apoptotic bodies and collagen deposition, resulting in decreased necrotic core formation. Likewise, renal lesions were significantly attenuated in D-CAR-octylester-treated vs. untreated mice, with lower inflammation, apoptosis, and fibrosis. This was associated with increased urinary levels of HNE-CAR adducts and reduced protein carbonylation, circulating and tissue ALEs, expression of receptors for these products, and systemic and tissue oxidative stress. Conclusions and Implications.  These data indicate RCS quenching with a D-CAR ester is highly effective in attenuating experimental atherosclerosis and renal disease by reducing carbonyl stress and inflammation and that this may represent a promising therapeutic strategy in humans.