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Updated: Feb 9, 2026
Quantification of Atherosclerosis in Mice
Published on: June 12, 2019
Human Aldose Reductase Expression Prevents Atherosclerosis Regression in Diabetic Mice
Chujun Yuan1,2, Jiyuan Hu3, Saj Parathath1,2
1Marc and Ruti Bell Vascular Biology Program, Leon Charney Division of Cardiology, New York University School of Medicine, New York, NY.
Abstract:
Guidelines to reduce cardiovascular risk in diabetes include aggressive LDL lowering, but benefits are attenuated compared with those in patients without diabetes. Consistent with this, we have reported in mice that hyperglycemia impaired atherosclerosis regression. Aldose reductase (AR) is thought to contribute to clinical complications of diabetes by directing glucose into pathways producing inflammatory metabolites. Mice have low levels of AR, thus raising them to human levels would be a more clinically relevant model to study changes in diabetes under atherosclerosis regression conditions. Donor aortae from Western diet-fed Ldlr mice were transplanted into normolipidemic wild-type, Ins2Akita (Akita , insulin deficient), human AR (hAR) transgenic, or Akita /hAR mice. Akita mice had impaired plaque regression as measured by changes in plaque size and the contents of CD68+ cells (macrophages), lipids, and collagen. Supporting synergy between hyperglycemia and hAR were the even more pronounced changes in these parameters in Akita /hAR mice, which had atherosclerosis progression in spite of normolipidemia. Plaque CD68+ cells from the Akita /hAR mice had increased oxidant stress and expression of inflammation-associated genes but decreased expression of anti-inflammatory genes. In summary, hAR expression amplifies impaired atherosclerosis regression in diabetic mice, likely by interfering with the expected reduction in plaque macrophage inflammation.
Insights
Human aldose reductase (AR) worsens atherosclerosis regression in diabetic mice, exacerbating cardiovascular risk. This suggests AR may be a therapeutic target for managing atherosclerosis in diabetes.
Area of Science:
- Cardiovascular Research
- Diabetes Complications
- Atherosclerosis Pathogenesis
Background:
- Cardiovascular risk reduction in diabetes often involves aggressive LDL lowering, but benefits are less pronounced than in non-diabetic individuals.
- Hyperglycemia is known to impair atherosclerosis regression, and aldose reductase (AR) contributes to diabetic complications by producing inflammatory metabolites.
- A mouse model with human-level AR is needed to better study diabetes-related atherosclerosis regression.
Purpose of the Study:
- To investigate the role of human aldose reductase (hAR) in exacerbating impaired atherosclerosis regression in a diabetic mouse model.
- To determine if hAR amplifies the negative effects of hyperglycemia on atherosclerotic plaque characteristics.
Main Methods:
- Atherosclerotic aortae from Western diet-fed Ldlr mice were transplanted into normolipidemic wild-type, Akita (insulin-deficient), hAR transgenic, or Akita/hAR mice.
- Plaque regression was assessed by measuring plaque size, macrophage content (CD68+ cells), lipids, and collagen.
- Inflammatory markers, oxidant stress, and gene expression in plaque macrophages were analyzed.
Main Results:
- Akita mice exhibited impaired plaque regression compared to controls.
- Akita/hAR mice showed even more pronounced plaque regression impairment, with signs of atherosclerosis progression despite normolipidemia.
- Macrophages in Akita/hAR mice displayed increased oxidant stress and inflammation-associated gene expression, with decreased anti-inflammatory gene expression.
Conclusions:
- Human aldose reductase expression significantly amplifies impaired atherosclerosis regression in diabetic mice.
- hAR likely interferes with the expected reduction in plaque macrophage inflammation, contributing to worsened cardiovascular outcomes in diabetes.
- Targeting hAR may offer a therapeutic strategy to improve atherosclerosis regression in diabetic patients.
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