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A Mouse Model for Pathogen-induced Chronic Inflammation at Local and Systemic Sites
Published on: August 8, 2014
Myeloid GSK3α Deficiency Reduces Lesional Inflammation and Neovascularization during Atherosclerotic Progression
Sarvatit Patel1, Nisarg Shah1, Brooke D'Mello1,2
1The Thrombosis and Atherosclerosis Research Institute, Hamilton, ON L8L 2X2, Canada.
Abstract:
The molecular mechanisms by which cardiovascular risk factors promote the development of atherosclerosis are poorly understood. We have recently shown that genetic ablation of myeloid glycogen synthase kinase (GSK)-3α attenuates atherosclerotic lesion development in low-density lipoprotein receptor-deficient (Ldlr-/-) mice. However, the precise contributions of GSK3α/β in atherogenesis are not known. The aim of this study is to investigate the effect of GSK3α and/or β deficiency on lesional inflammation and plaque vascularization. Five-week-old female Ldlr-/- mice were fed a high-fat diet for 10 weeks to establish atherosclerotic lesions. Mice were harvested at 15 weeks of age and atherosclerotic lesions were characterized. The results indicate that, in addition to significantly reducing plaque volume, GSK3α-deficiency decreases inflammation, reduces vasa vasorum density at the aortic sinus, and reduces plasma c-reactive protein (CRP) levels. GSK3β-deficiency is associated with decreased plasma CRP levels but does not affect lesional inflammation or vascularization. These results suggest GSK3α may be an applicable target for the development of novel anti-atherogenic therapies.
Insights
Genetic ablation of glycogen synthase kinase-3 alpha (GSK3α) reduced atherosclerosis, inflammation, and plaque vascularization in mice. GSK3α deficiency may offer a novel therapeutic target for preventing atherosclerosis.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Inflammation Research
Background:
- Cardiovascular risk factors' role in atherosclerosis pathogenesis remains unclear.
- Glycogen synthase kinase-3 alpha (GSK3α) genetic ablation previously showed reduced atherosclerotic lesion development.
- The specific roles of GSK3α and GSK3β in atherogenesis require further investigation.
Purpose of the Study:
- To investigate the impact of GSK3α and/or GSK3β deficiency on atherosclerotic lesion inflammation and vascularization.
- To elucidate the molecular mechanisms underlying GSK3's role in atherosclerosis.
Main Methods:
- Utilized low-density lipoprotein receptor-deficient (Ldlr-/-) mice fed a high-fat diet for 10 weeks.
- Established atherosclerotic lesions in 5-week-old female mice, harvesting at 15 weeks.
- Characterized atherosclerotic lesions, focusing on inflammation, plaque volume, and vasa vasorum density.
Main Results:
- GSK3α deficiency significantly reduced plaque volume, lesional inflammation, and aortic sinus vasa vasorum density.
- GSK3α-deficient mice exhibited decreased plasma c-reactive protein (CRP) levels.
- GSK3β deficiency lowered plasma CRP but did not impact lesional inflammation or vascularization.
Conclusions:
- GSK3α plays a critical role in promoting atherosclerotic lesion development, inflammation, and vascularization.
- GSK3α represents a potential therapeutic target for developing novel anti-atherogenic treatments.
- GSK3β's role in atherogenesis appears distinct from GSK3α, with limited impact on lesion characteristics.
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