The Thrombosis and Atherosclerosis Research Institute, Hamilton, ON L8L 2X2, Canada.
Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A1, Canada.
Int J Mol Sci. 2024 Oct 10;25(20):10897. doi: 10.3390/ijms252010897.
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.
心血管风险因素促进动脉粥样硬化发展的分子机制尚未完全阐明。我们最近发现，敲除骨髓糖原合酶激酶（GSK）-3α可减轻载脂蛋白 E 基因敲除（ApoE）小鼠的动脉粥样硬化病变发展。然而，GSK3α/β 在动脉粥样硬化形成中的确切作用尚不清楚。本研究旨在探讨 GSK3α 和/或β 缺乏对病变炎症和斑块血管生成的影响。将 5 周龄雌性载脂蛋白 E 基因敲除（ApoE）小鼠用高脂肪饮食喂养 10 周以建立动脉粥样硬化病变。在 15 周龄时采集小鼠，对动脉粥样硬化病变进行特征分析。结果表明，除了显著减少斑块体积外，GSK3α 缺乏还可降低炎症反应、减少主动脉窦中的血管周间隙密度，并降低血浆 C 反应蛋白（CRP）水平。GSK3β 缺乏与降低的血浆 CRP 水平相关，但不影响病变炎症或血管生成。这些结果表明 GSK3α 可能是开发新型抗动脉粥样硬化治疗方法的一个有应用前景的靶点。
