Department of Nephrology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centre, Amsterdam, The Netherlands.
Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centre, Amsterdam, The Netherlands.
Thromb Haemost. 2022 Jun;122(6):1047-1057. doi: 10.1055/a-1711-1055. Epub 2022 Feb 8.
Galectins have numerous cellular functions in immunity and inflammation. Short-term galectin-2 (Gal-2) blockade in ischemia-induced arteriogenesis shifts macrophages to an anti-inflammatory phenotype and improves perfusion. Gal-2 may also affect other macrophage-related cardiovascular diseases.
This study aims to elucidate the effects of Gal-2 inhibition in atherosclerosis.
mice were given a high-cholesterol diet (HCD) for 12 weeks. After 6 weeks of HCD, intermediate atherosclerotic plaques were present. To study the effects of anti-Gal-2 nanobody treatment on the progression of existing atherosclerosis, treatment with two llama-derived anti-Gal-2 nanobodies (clones 2H8 and 2C10), or vehicle was given for the remaining 6 weeks.
Gal-2 inhibition reduced the progression of existing atherosclerosis. Atherosclerotic plaque area in the aortic root was decreased, especially so in mice treated with 2C10 nanobodies. This clone showed reduced atherosclerosis severity as reflected by a decrease in fibrous cap atheromas in addition to decreases in plaque size.The number of plaque resident macrophages was unchanged; however, there was a significant increase in the fraction of CD206 macrophages. 2C10 treatment also increased plaque α-smooth muscle content, and Gal-2 may have a role in modulating the inflammatory status of smooth muscle cells. Remarkably, both treatments reduced serum cholesterol concentrations including reductions in very low-density lipoprotein, low-density lipoprotein, and high-density lipoprotein while triglyceride concentrations were unchanged.
Prolonged and frequent treatment with anti-Gal-2 nanobodies reduced plaque size, slowed plaque progression, and modified the phenotype of plaque macrophages toward an anti-inflammatory profile. These results hold promise for future macrophage modulating therapeutic interventions that promote arteriogenesis and reduce atherosclerosis.
半乳糖凝集素在免疫和炎症中具有多种细胞功能。在缺血性动脉生成诱导的情况下，短期阻断半乳糖凝集素-2（Gal-2）可使巨噬细胞向抗炎表型转变，并改善灌注。Gal-2 也可能影响其他与巨噬细胞相关的心血管疾病。
本研究旨在阐明 Gal-2 抑制在动脉粥样硬化中的作用。
给予小鼠高胆固醇饮食（HCD）12 周。在 HCD 6 周后，出现中等程度的动脉粥样硬化斑块。为了研究抗 Gal-2 纳米抗体治疗对现有动脉粥样硬化进展的影响，用两种来源于骆驼的抗 Gal-2 纳米抗体（克隆 2H8 和 2C10）或载体治疗剩余的 6 周。
Gal-2 抑制可减缓现有动脉粥样硬化的进展。主动脉根部粥样斑块面积减少，尤其是用 2C10 纳米抗体治疗的小鼠。该克隆显示出严重程度降低，纤维帽粥样斑块减少，同时斑块大小减小。斑块驻留巨噬细胞数量不变；然而，CD206 巨噬细胞的比例显著增加。2C10 治疗还增加了斑块的α-平滑肌含量，Gal-2 可能在调节平滑肌细胞的炎症状态中发挥作用。值得注意的是，两种治疗均降低了血清胆固醇浓度，包括降低极低密度脂蛋白、低密度脂蛋白和高密度脂蛋白，而甘油三酯浓度不变。
长期频繁使用抗 Gal-2 纳米抗体可减少斑块大小，减缓斑块进展，并使斑块巨噬细胞表型向抗炎表型转变。这些结果为未来促进动脉生成和减少动脉粥样硬化的巨噬细胞调节治疗干预提供了希望。
