Aldose Reductase Protects Against Early Atherosclerotic Lesion Formation in Apolipoprotein E-Null Mice

Abstract

Rationale Atherosclerotic lesion formation is associated with the accumulation of oxidized lipids. Products of lipid oxidation, particularly aldehydes, stimulate cytokine production and enhance monocyte adhesion, however their contribution to atherosclerotic lesion formation remains unclear. Objective To test the hypothesis that inhibition of aldehyde removal by aldose reductase (AR), which metabolizes both free and phospholipid aldehydes, would exacerbate atherosclerotic lesion formation. Methods and Results In atherosclerotic lesions of apoE-null mice, AR protein was localized with macrophage-rich regions and its abundance increased with lesion progression. Treatment of apoE-null mice with AR inhibitors sorbinil or tolrestat increased early lesion formation, but did not affect the formation of advanced lesions. Early lesions of AR−/−/apoE−/− mice maintained on high fat diet were significantly larger when compared with age-matched AR+/+/apoE−/− mice. The increase in lesion area due to deletion of the AR gene was seen in both male and female mice. Pharmacological inhibition or genetic ablation of AR also increased the lesion formation in male mice made diabetic by streptozotocin treatment. Lesions in AR−/−/apoE−/− mice exhibited increased collagen and macrophage content and a decrease in smooth muscle cells. AR−/−/apoE−/− mice displayed a greater accumulation of the AR substrate 4-hydroxy trans-2-nonenal (HNE) in the plasma and protein-HNE adducts in arterial lesions than AR+/+/apoE−/− mice. Conclusions These observations indicate that AR is upregulated in atherosclerotic lesions and it protects against early stages of atherogenesis by removing toxic aldehydes generated in oxidized lipids.

Reductive metabolism increases the proinflammatory activity of aldehyde phospholipids

“…For example, in LDL-R null mice, inhibition of NF-B in macrophages decreases atherosclerotic lesion formation ( 56 ), whereas IL-6-null mice develop more fatty streaks than WT mice ( 57 ). Similarly, despite the clear infl ammation-enhancing effects of PLA 2 and AR in macrophages reported here, atherosclerotic lesion formation is higher in AR-and apoEnull mice than it is in WT-apoE-null mice ( 58 ), and Lp-PLA 2 gene transfer reduces spontaneous atherosclerosis ( 46 ). Clearly, extensive additional investigations are required to fully understand how infl ammation contributes to atherosclerotic lesion formation and how it is triggered by oxidized phospholipids and regulated by their metabolism.…”

Role of Aldose Reductase in the Metabolism and Detoxification of Carnosine-Acrolein Conjugates

“…This conjugative reaction is further enhanced by glutathione S-transferases. Our previous studies have shown that the glutathione conjugates of aldehydes are further metabolized by a reductive transformation catalyzed by aldose reductase (AR) (17,18) and that inhibition of this metabolic transformation increases aldehyde accumulation and exacerbates ischemic injury (19) and atherosclerotic lesion formation (6). These observations support the view that reduction diminishes the ability of aldehyde-glutathione conjugates to induce tissue toxicity.…”

“…These aldehydes react readily with cellular nucleophiles such as glutathione, histidine, lysine, or arginine residues in proteins and guanosine bases in DNA. Previous studies have shown that aldehyde-modified proteins accumulate in diseased tissue during atherosclerosis (5,6), myocardial ischemia (7,8), arteritis (9), diabetes, and Alzheimer (10) and Parkinson (11,12). Increased accumulation of aldehyde-modified DNA bases has also been associated with oxidative stress (13)(14)(15).…”

Atherogenesis and metabolic dysregulation in LDL receptor–knockout rats

“…Blood was collected every 4 weeks from the tail vein after a 6-hour fast, and blood glucose was measured by an ACCU-CHEK Aviva glucometer. Levels of cholesterol and triglycerides in the plasma were measured as described (61,62). For the quantitation of cholesterol and triglycerides in the liver, the tissue was pulverized and lipids were extracted as described by Bligh and Dyer (63).…”