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11:10
Hyperinsulinemic-euglycemic Clamps in Conscious, Unrestrained Mice
Published on: November 16, 2011
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Hyperglycemia impairs atherosclerosis regression in mice.
Nathalie Gaudreault1, Nikit Kumar1, Victor R Olivas1
1Surgical Service, VA Medical Center San Francisco, San Francisco, California; Division of Vascular and Endovascular Surgery, Department of Surgery, University of California San Francisco, San Francisco, California.
The American Journal of Pathology
|October 12, 2013
Summary
Hyperglycemia, or high blood sugar, hinders atherosclerosis regression in diabetic patients by impairing cholesterol transport in macrophages. This reduces lipid loss and lesion size reduction, impacting cardiovascular health.
Area of Science:
- Cardiovascular Biology
- Metabolic Disease Research
- Atherosclerosis Pathogenesis
Background:
- Diabetic patients exhibit increased susceptibility to atherosclerosis and cardiovascular complications.
- The impact of hyperglycemia on the regression of atherosclerotic plaques remains incompletely understood.
- Lesional macrophages play a critical role in the development and potential regression of atherosclerosis.
Purpose of the Study:
- To investigate the effects of hyperglycemia on atherosclerosis regression in a mouse model.
- To determine if hyperglycemia modulates the biological function of lesional macrophages during plaque regression.
- To elucidate the molecular mechanisms by which hyperglycemia affects lipid metabolism and cholesterol transport in atherosclerotic lesions.
Main Methods:
- Utilized HypoE (Apoe(h/h)Mx1-Cre) mice, which develop atherosclerosis on a high-fat diet and undergo regression upon lipid lowering and restored apolipoprotein E (apoE) expression.
- Induced hyperglycemia using streptozotocin treatment in euglycemic and hyperglycemic HypoE mice.
- Assessed lesion morphology, lipid content, and lesional macrophage function via laser-capture microdissection and gene expression analysis.
Main Results:
- Hyperglycemia significantly impaired lesion size reduction (36% vs. 14%) and lipid loss (38% vs. 26%) during atherosclerosis regression.
- Macrophage content reduction and vascular wall remodeling were similar between euglycemic and hyperglycemic groups.
- Gene expression analysis revealed hyperglycemia dysregulated cholesterol transport (via ABCA1, ABCG1, CD36, SR-B1) and wound healing pathways in lesional macrophages.
Conclusions:
- Hyperglycemia impairs atherosclerosis regression by hindering lipid loss and plaque size reduction, even after plasma lipid normalization.
- The detrimental effects of hyperglycemia are mediated through the modulation of lesional macrophage cholesterol transport and related pathways.
- These findings highlight a critical mechanism by which diabetes exacerbates cardiovascular risk through impaired plaque regression.
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