Human aldose reductase expression accelerates diabetic atherosclerosis in transgenic mice

Abstract

Direct evidence that hyperglycemia, rather than concomitant increases in known risk factors, induces atherosclerosis is lacking. Most diabetic mice do not exhibit a higher degree of atherosclerosis unless the development of diabetes is associated with more severe hyperlipidemia. We hypothesized that normal mice were deficient in a gene that accelerated atherosclerosis with diabetes. The gene encoding aldose reductase (AR), an enzyme that mediates the generation of toxic products from glucose, is expressed at low levels in murine compared with human tissues. Mice in which diabetes was induced through streptozotocin (STZ) treatment, but not nondiabetic mice, expressing human AR (hAR) crossed with LDL receptor-deficient (Ldlr -/-) C57BL/6 male mice had increased aortic atherosclerosis. Diabetic hAR-expressing heterozygous LDL receptor-knockout mice (Ldlr +/-) fed a cholesterol/cholic acid-containing diet also had increased aortic lesion size. Lesion area at the aortic root was increased by STZ treatment alone but was further increased by hAR expression. Macrophages from hARtransgenic mice expressed more scavenger receptors and had greater accumulation of modified lipoproteins than macrophages from nontransgenic mice. Expression of genes that regulate regeneration of glutathione was reduced in the hAR-expressing aortas. Thus, hAR increases atherosclerosis in diabetic mice. Inhibitors of AR or other enzymes that mediate glucose toxicity could be useful in the treatment of diabetic atherosclerosis. IntroductionAlthough people with both type 1 and type 2 diabetes develop increased atherosclerosis, which leads to more heart attacks and strokes, direct evidence that this is mediated by hyperglycemia is lacking. In part, this is because additional atherogenic factors such as lipid abnormalities and hypertension accompany the diabetes (1, 2). Efforts to demonstrate the presumed toxic effects of hyperglycemia in experimental animals have been similarly hindered (3). Diabetes has been superimposed onto wild-type and atherosclerosis-prone mice in an attempt to reproduce the relationship between diabetes and macrovascular disease. However, a clear model of diabetes-induced accelerated atherosclerosis is lacking. In several situations, genetic insulin resistance and streptozotocin-mediated (STZ-mediated) destruction of islet cells produced greater hyperlipidemia and, not surprisingly, more atherosclerosis (4). This was noted in both LDL receptorknockout (Ldlr -/-) (5, 6) and apoE-knockout mice (7). In a recent study, chow-fed Ldlr -/-diabetic mice had more atherosclerosis at the aortic root, but when these mice were fed cholesterol-containing diet, the atherosclerosis correlated with plasma cholesterol and not glucose (8). Thus, as in many previous reports, the more advanced vascular lesions in these mice were attributable to greater hyperlipidemia and not hyperglycemia or defective insulin actions.

Nutritional B vitamin deficiency alters the expression of key proteins associated with vascular smooth muscle cell proliferation and migration in the aorta of atherosclerotic apolipoprotein E null mice

“…Suboptimum folate status and hyperhomocysteinemia are linked with hyperlipidemia and oxidative stress, major risk factors for vascular disease (Kris-Etherton et al 2002;Lohm et al 2002;Mikael et al 2006;Devlin et al 2007). Here, B vitamin depletion was associated with significant changes in vascular adventitial lipid metabolism and protein markers of cellular stress known to be altered in atherosclerosis (Brownlee 2001;Vikramadithyan et al 2005) only when combined with this additional oxidative insult. Glutathione S-transferase Mu was elevated, as was aldose reductase, a protein that induces atherosclerosis in mice (Vikramadithyan et al 2005) and is upregulated in human foam cells and plaque macrophages (Gleissner et al 2008).…”

“…Here, B vitamin depletion was associated with significant changes in vascular adventitial lipid metabolism and protein markers of cellular stress known to be altered in atherosclerosis (Brownlee 2001;Vikramadithyan et al 2005) only when combined with this additional oxidative insult. Glutathione S-transferase Mu was elevated, as was aldose reductase, a protein that induces atherosclerosis in mice (Vikramadithyan et al 2005) and is upregulated in human foam cells and plaque macrophages (Gleissner et al 2008). Peroxiredoxin expression was decreased in this study.…”

Mechanisms by which diabetes increases cardiovascular disease

“…Recently, the glucose flux through the polyol pathway has been linked to atherosclerosis in LDL receptor (LDLR) deficient mice [11]. Overexpression of human AR in these mice (which physiologically display only low AR expression) resulted in increased atherosclerotic lesion size if the mice were made diabetic by injection of streptozotocin (STZ), which specifically destroys pancreatic β-cells and thereby mimics type 1 diabetes.…”

Diabetic Vascular Disease

“…93,94 In one study, imposition of STZ diabetes increased lesion size at the aortic root in these mice. 95 …”

“…95 Moreover, investigators who have sequenced the mouse AR gene claim that a genetic alteration in mice leads to an AR with reduced activity (K. Gabbay, personal communication). Transgenic mice expressing this enzyme via mouse major histocompatibility antigen class I promoter have expression levels that are more similar to those in humans.…”