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

Area of Science:

• Biochemistry
• Cardiovascular Biology
• Metabolic Disease Research

Background:

• Aberrant glucose metabolism in diabetes can lead to vascular damage.
• The polyol pathway, mediated by aldose reductase (AR), is a potential contributor to this damage.
• Previous research suggests AR may have antiatherogenic properties by reducing toxic lipid aldehydes.

Purpose of the Study:

• To investigate the role of aldose reductase (AR) in atherosclerosis development in a diabetic mouse model.
• To determine if increased AR expression in the artery wall exacerbates vascular damage.
• To assess the impact of pharmacological AR inhibition on atherosclerosis.

Main Methods:

• Utilized transgenic mice expressing human AR (hAR) on an apolipoprotein E knockout background.
• Examined both generalized hAR overexpression and hAR expression driven by the Tie 2 promoter.
• Quantified atherosclerosis development in streptozotocin-induced diabetic mice.
• Administered pharmacological inhibitors of AR to assess their effect on lesion size.

Main Results:

• Overexpression of hAR in transgenic mice significantly increased atherosclerosis lesion size in diabetic conditions.
• Both generalized and Tie 2 promoter-driven hAR expression led to greater lesion development.
• Pharmacological inhibition of AR resulted in a reduction of atherosclerosis lesion size.

Conclusions:

• Despite potential roles in reducing toxic aldehydes, transgenic AR expression in the artery wall promotes atherosclerosis in diabetic mice.
• These findings highlight a pro-atherogenic role for AR in the vascular context of diabetes.
• Targeting AR may represent a therapeutic strategy to mitigate vascular complications in diabetes.