Aberdeen Cardiovascular and Diabetes Centre, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK.
Department of Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
J Transl Med. 2023 Oct 12;21(1):715. doi: 10.1186/s12967-023-04598-2.
Atherosclerosis is a chronic inflammatory process induced by the influx and entrapment of excess lipoproteins into the intima media of arteries. Previously, our lab demonstrated that systemic PTP1B inhibition protects against atherosclerosis in preclinical LDLR models. Similarly, it was shown that myeloid-specific PTP1B ablation decreases plaque formation and ameliorates dyslipidaemia in the ApoE model of atherosclerosis. We hypothesized that the relevant improvements in dyslipidaemia following modification of PTP1B activation may either result from changes in hepatic cholesterol biosynthesis and/or increased uptake and degradation by liver-resident macrophages. We examined this in animal models and patients with coronary artery disease.
In this study, we determined the cholesterol-lowering effect of myeloid-PTP1B deletion in mice fed a high-fat high-cholesterol diet and examined effects on total cholesterol levels and lipoprotein profiles. We also determined the effects of PTP1B inhibition to oxLDL-C challenge on foam cell formation and cholesterol efflux in human monocytes/macrophages.
We present evidence that myeloid-PTP1B deficiency significantly increases the affinity of Kupffer cells for ApoB containing lipoproteins, in an IL10-dependent manner. We also demonstrate that PTP1B inhibitor, MSI-1436, treatment decreased foam cell formation in Thp1-derived macrophages and increased macrophage cholesterol efflux to HDL in an AMPK-dependent manner. We present evidence of three novel and distinct mechanisms regulated by PTP1B: an increase in cholesterol efflux from foam cells, decreased uptake of lipoproteins into intra-lesion macrophages in vitro and a decrease of circulating LDL-C and VLDL-C in vivo.
Overall, these results suggest that myeloid-PTP1B inhibition has atheroprotective effects through improved cholesterol handling in atherosclerotic lesions, as well as increased reverse cholesterol transport. Trial registration Research registry, researchregistry 3235. Registered 07 November 2017, https://www.researchregistry.com/browse-the-registry#home/registrationdetails/5a01d0fce7e1904e93e0aac5/ .
动脉粥样硬化是一种由过量脂蛋白流入并滞留在动脉内膜中层引起的慢性炎症过程。此前，我们实验室证明，全身性 PTP1B 抑制可预防临床前 LDLR 模型中的动脉粥样硬化。同样，有研究表明，髓系特异性 PTP1B 缺失可减少斑块形成并改善动脉粥样硬化的 ApoE 模型中的血脂异常。我们假设，PTP1B 激活修饰后血脂异常的相关改善可能源自于肝脏胆固醇生物合成的变化和/或肝驻留巨噬细胞的摄取和降解增加。我们在动物模型和冠心病患者中对此进行了研究。
在这项研究中，我们在高脂高胆固醇饮食喂养的小鼠中确定了髓系 PTP1B 缺失的降胆固醇作用，并研究了其对总胆固醇水平和脂蛋白谱的影响。我们还确定了 PTP1B 抑制剂 MSI-1436 对 oxLDL-C 刺激下人单核细胞/巨噬细胞泡沫细胞形成和胆固醇流出的影响。
我们提供的证据表明，髓系 PTP1B 缺陷以 IL10 依赖的方式显著增加了库普弗细胞对含 ApoB 的脂蛋白的亲和力。我们还证明，PTP1B 抑制剂 MSI-1436 处理可减少 Thp1 衍生的巨噬细胞中泡沫细胞的形成，并以 AMPK 依赖的方式增加巨噬细胞胆固醇向 HDL 的流出。我们提供了三种受 PTP1B 调节的新型且不同机制的证据：泡沫细胞胆固醇流出增加、体外病变内巨噬细胞对脂蛋白摄取减少以及体内循环 LDL-C 和 VLDL-C 减少。
总体而言，这些结果表明，髓系 PTP1B 抑制通过改善动脉粥样硬化病变中的胆固醇处理以及增加逆向胆固醇转运，具有抗动脉粥样硬化作用。试验注册 研究注册，researchregistry 3235。于 2017 年 11 月 7 日注册，https://www.researchregistry.com/browse-the-registry#home/registrationdetails/5a01d0fce7e1904e93e0aac5/。
