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Human aldose reductase expression accelerates atherosclerosis in diabetic apolipoprotein E-/- mice.

ABSTRACT: There are several pathways that mediate the aberrant metabolism of glucose and that might induce greater vascular damage in the setting of diabetes. The polyol pathway mediated by aldose reductase (AR) has been postulated to be one such pathway. However, it has been reported that AR reduces toxic lipid aldehydes and, under some circumstances, might be antiatherogenic.Atherosclerosis development was quantified in 2 lines of transgenic mice expressing human AR (hAR) crossed on the apolipoprotein E knockout background. The transgenes were used to increase the normally low levels of this enzyme in wild-type mice. Both generalized hAR overexpression and hAR expression via the Tie 2 promoter increased lesion size in streptozotocin diabetic mice. In addition, pharmacological inhibition of AR reduced lesion size.Although in some settings AR expression might reduce levels of toxic aldehydes, transgenic expression of this enzyme within the artery wall leads to greater atherosclerosis.

SUBMITTER: Vedantham S

PROVIDER: S-EPMC3278231 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Human aldose reductase expression accelerates atherosclerosis in diabetic apolipoprotein E-/- mice.

Vedantham Srinivasan S Noh HyeLim H Ananthakrishnan Radha R Son Ni N Hallam Kellie K Hu Yunying Y Yu Shuiquing S Shen Xiaoping X Rosario Rosa R Lu Yan Y Ravindranath Thyyar T Drosatos Konstantinos K Huggins Lesley Ann LA Schmidt Ann Marie AM Goldberg Ira J IJ Ramasamy Ravichandran R

Arteriosclerosis, thrombosis, and vascular biology 20110602 8

<h4>Objective</h4>There are several pathways that mediate the aberrant metabolism of glucose and that might induce greater vascular damage in the setting of diabetes. The polyol pathway mediated by aldose reductase (AR) has been postulated to be one such pathway. However, it has been reported that AR reduces toxic lipid aldehydes and, under some circumstances, might be antiatherogenic.<h4>Methods and results</h4>Atherosclerosis development was quantified in 2 lines of transgenic mice expressing ...[more]

PMID: 21636809

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Project description:Fat inflammation may play an important role in comorbidities associated with obesity such as atherosclerosis.To first establish feasibility of fat transplantation, epididymal fat pads were harvested from wild-type C57BL/6J mice and transplanted into leptin-deficient (Lep(ob/ob)) mice. Fat transplantation produced physiological leptin levels and prevented obesity and infertility in Lep(ob/ob) mice. However, the transplanted fat depots were associated with chronically increased macrophage infiltration with characteristics identical to those observed in fat harvested from obese animals. The inflammation in transplanted adipose depots was regulated by the same factors that have been implicated in endogenous fat inflammation such as monocyte chemoattractant protein-1. To determine whether this inflamed adipose depot could affect vascular disease in mice, epididymal fat depots were transplanted into atherosclerosis-prone apolipoprotein E-deficient ApoE(-/-) mice. Plasma from ApoE(-/-) mice receiving fat transplants contained increased leptin, resistin, and monocyte chemoattractant protein-1 compared with plasma from sham-operated ApoE(-/-) mice. Furthermore, mice transplanted with visceral fat developed significantly more atherosclerosis compared with sham-operated animals, whereas transplants with subcutaneous fat did not affect atherosclerosis despite a similar degree of fat inflammation. Treatment of transplanted ApoE(-/-) mice with pioglitazone decreased macrophage content of the transplanted visceral fat pad and reduced plasma monocyte chemoattractant protein-1. Importantly, pioglitazone also reduced atherosclerosis triggered by inflammatory visceral fat but had no protective effect on atherosclerosis in the absence of the visceral fat transplantation.Our results indicate that visceral adipose-related inflammation accelerates atherosclerosis in mice. Drugs such as thiazolidinediones might be a useful strategy to specifically attenuate the vascular disease induced by visceral inflammatory fat.

Dataset Information

Human aldose reductase expression accelerates atherosclerosis in diabetic apolipoprotein E-/- mice.

Publications

Human aldose reductase expression accelerates atherosclerosis in diabetic apolipoprotein E-/- mice.

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