Institute of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK.
Institute of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK.
Mol Metab. 2017 Jun 13;6(8):845-853. doi: 10.1016/j.molmet.2017.06.003. eCollection 2017 Aug.
Cardiovascular disease (CVD) is the most prevalent cause of mortality among patients with Type 1 or Type 2 diabetes, due to accelerated atherosclerosis. Recent evidence suggests a strong link between atherosclerosis and insulin resistance due to impaired insulin receptor (IR) signaling. Moreover, inflammatory cells, in particular macrophages, play a key role in pathogenesis of atherosclerosis and insulin resistance in humans. We hypothesized that inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B), the major negative regulator of the IR, specifically in macrophages, would have beneficial anti-inflammatory effects and lead to protection against atherosclerosis and CVD.
We generated novel macrophage-specific PTP1B knockout mice on atherogenic background (ApoE/LysM-PTP1B). Mice were fed standard or pro-atherogenic diet, and body weight, adiposity (echoMRI), glucose homeostasis, atherosclerotic plaque development, and molecular, biochemical and targeted lipidomic eicosanoid analyses were performed.
Myeloid-PTP1B knockout mice on atherogenic background (ApoE/LysM-PTP1B) exhibited a striking improvement in glucose homeostasis, decreased circulating lipids and decreased atherosclerotic plaque lesions, in the absence of body weight/adiposity differences. This was associated with enhanced phosphorylation of aortic Akt, AMPKα and increased secretion of circulating anti-inflammatory cytokine interleukin-10 (IL-10) and prostaglandin E2 (PGE), without measurable alterations in IR phosphorylation, suggesting a direct beneficial effect of myeloid-PTP1B targeting.
Here we demonstrate that inhibiting the activity of PTP1B specifically in myeloid lineage cells protects against atherosclerotic plaque formation, under atherogenic conditions, in an ApoE mouse model of atherosclerosis. Our findings suggest for the first time that macrophage PTP1B targeting could be a therapeutic target for atherosclerosis treatment and reduction of CVD risk.
由于动脉粥样硬化的加速，心血管疾病（CVD）是 1 型或 2 型糖尿病患者中最常见的死亡原因。最近的证据表明，由于胰岛素受体（IR）信号受损，动脉粥样硬化和胰岛素抵抗之间存在很强的联系。此外，炎症细胞，特别是巨噬细胞，在人类动脉粥样硬化和胰岛素抵抗的发病机制中发挥关键作用。我们假设，抑制蛋白酪氨酸磷酸酶 1B（PTP1B）的活性，IR 的主要负调节剂，特别是在巨噬细胞中，将具有有益的抗炎作用，并导致对动脉粥样硬化和 CVD 的保护。
我们在动脉粥样硬化背景（ApoE/LysM-PTP1B）上产生了新型的巨噬细胞特异性 PTP1B 敲除小鼠。给小鼠喂食标准或致动脉粥样硬化饮食，并进行体重、肥胖（回声 MRI）、葡萄糖稳态、动脉粥样硬化斑块形成以及分子、生化和靶向脂质组学花生四烯酸代谢产物分析。
在动脉粥样硬化背景（ApoE/LysM-PTP1B）上缺乏体重/肥胖差异的情况下，髓系 PTP1B 敲除小鼠的葡萄糖稳态明显改善，循环脂质减少，动脉粥样硬化斑块病变减少。这与主动脉 Akt、AMPKα 的磷酸化增强以及循环抗炎细胞因子白细胞介素 10（IL-10）和前列腺素 E2（PGE）的分泌增加有关，而 IR 磷酸化没有可测量的改变，表明髓系 PTP1B 靶向的直接有益作用。
在这里，我们证明在动脉粥样硬化 ApoE 小鼠模型中，特异性抑制髓系细胞中的 PTP1B 活性可防止动脉粥样硬化斑块形成。我们的研究结果首次表明，巨噬细胞 PTP1B 靶向可能是动脉粥样硬化治疗和降低 CVD 风险的治疗靶点。
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