Abstract 262: Inhibition Of Aldose Reductase Exacerbates Atherosclerotic Lesion Formation In apo E-Null Mice
Oxidation of LDL generates highly reactive free aldehydes, such as, 4, hydroxy-trans-2-nonenal (HNE) as well as phospholipid aldehydes, e.g., 1, palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine. These aldehydes elicit a variety of pro-atherogenic functions in vitro including, induction of adhesion molecules on vascular endothelium, monocyte adhesion and smooth muscle cell proliferation. We have previously shown that aldose reductase (AR) efficiently catalyzes the reduction of these aldehydes in aortic endothelial cells, smooth muscle cells and monocytes. In the present study we examined the effect of pharmacological inhibition of AR on the atherosclerotic lesion formation in apo E-null mice. Eight weeks old apoE-null mice were fed a high fat-high cholesterol diet and treated without (n=9) or with AR inhibitors - tolrestat (0.2g/L/day; n=9) or sorbinil (0.2g/L/day; n=9) in drinking water for 4 weeks. Both sorbinil and tolrestat increased the atherosclerotic lesion formation by 1.6 - 2.0 fold in the aortic sinus (P<0.01) and the aortic arch (P<0.01), with no change in plasma cholesterol and triglycerides. Similarly, prolonged treatment (28 weeks) of 12 week old apoE-null mice maintained on the high fat diet with sorbinil (n=9) or tolrestat (n=9) enhanced the atherosclerotic lesion formation both in the aorta as well as the aortic roots by 1.6–1.8 fold (P<0.01), versus vehicle treated mice (n=9), without any significant change in plasma lipoproteins. However, feeding of sorbinil to 24 weeks old mice (n=9), exhibiting intermediate lesions, for 12 weeks had no effect on the vascular lesion formation, as compared to vehicle fed mice. Immunohistochemical analysis showed that accumulation of protein-HNE adducts and expression of AR increases with the lesion progression and co-localizes with endothelial cells (vWF) and macrophages (MOMA-2). Moreover, prolonged inhibition of AR in 12 weeks old mice resulted in 1.4 fold increase in the collagen level in the aortic roots (P<0.05). Collectively, these data suggest that aldehydes generated in oxidized LDL, contribute to atherosclerotic lesion formation and inhibition of aldehyde metabolism in dyslipidimic mice increases early atherogenesis by increasing aldehyde accumulation in vascular lesions.