Gasbarrino Karina, Zheng Huaien, Hafiane Anouar, Veinot John P, Lai Chi, Daskalopoulou Stella S
From the Division of Experimental Medicine (K.G., H.Z., S.S.D.) and Division of Biochemistry (A.H.), Department of Medicine, Faculty of Medicine, Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada; and Department of Pathology and Laboratory Medicine, University of Ottawa Heart Institute, Ontario, Canada (J.P.V., C.L.).
Stroke. 2017 Apr;48(4):915-924. doi: 10.1161/STROKEAHA.116.015145. Epub 2017 Mar 3.
Adiponectin, the most abundantly secreted anti-inflammatory adipokine, protects against all stages of atherosclerotic plaque formation by acting on its receptors, AdipoR1 (adiponectin receptor 1) and AdipoR2 (adiponectin receptor 2). Through binding of AdipoR1, adiponectin leads to the activation of the AMPK (adenosine monophosphate-activated protein kinase) pathway, whereas stimulation of PPAR-α (peroxisome proliferator-activated receptor-α) is attributed to the binding of AdipoR2. However, the role of adiponectin and its receptors in plaque instability remains to be characterized. Thus, we aimed to investigate whether the adiponectin-AdipoR pathway is associated with carotid atherosclerotic plaque instability.
The instability of plaque specimens obtained from patients who underwent a carotid endarterectomy (n=143) was assessed using gold standard histological classifications.
Using immunohistochemistry, we showed that adiponectin and AdipoR1/AdipoR2 are expressed in human carotid plaques and that their expression was localized most abundantly in areas of macrophage and foam cell accumulation. Unstable plaques expressed more adiponectin protein (Western blot, <0.05) and less AdipoR2 mRNA (2.11-fold decrease, <0.05) than stable plaques, whereas AdipoR1 expression remained similar between stable and unstable plaques. Beyond AdipoR1/AdipoR2 expression, a graded decrease in PPAR-α protein levels was observed in relation to carotid plaque instability (<0.001), whereas AMPK phosphorylation was increased (<0.05). Our in vitro model of plaque instability, involving the induction of foam cells from human THP-1 (Tamm-Horsfall protein 1) macrophages treated with acetylated low-density lipoprotein, supported our in vivo conclusions.
An overall abundance of adiponectin with a decrease in AdipoR2 expression and activity was observed in unstable plaques, suggesting that reduced signaling through the AdipoR2 pathway, and not through AdipoR1, may contribute to plaque instability.
脂联素是分泌最为丰富的抗炎性脂肪因子，通过作用于其受体脂联素受体1（AdipoR1）和脂联素受体2（AdipoR2），对动脉粥样硬化斑块形成的各个阶段均具有保护作用。脂联素通过与AdipoR1结合，激活腺苷酸活化蛋白激酶（AMPK）通路，而脂联素与AdipoR2结合则可刺激过氧化物酶体增殖物激活受体α（PPAR-α）。然而，脂联素及其受体在斑块不稳定性中的作用仍有待明确。因此，我们旨在研究脂联素-AdipoR通路是否与颈动脉粥样硬化斑块的不稳定性相关。
采用金标准组织学分类方法，对143例行颈动脉内膜切除术患者的斑块标本的不稳定性进行评估。
通过免疫组织化学方法，我们发现脂联素以及AdipoR1/AdipoR2在人类颈动脉斑块中均有表达，且其表达在巨噬细胞和泡沫细胞聚集区域最为丰富。与稳定斑块相比，不稳定斑块表达更多的脂联素蛋白（蛋白质印迹法，P<0.05），而AdipoR2 mRNA表达较少（降低2.11倍，P<0.05），而稳定斑块与不稳定斑块之间AdipoR1的表达相似。除AdipoR1/AdipoR2表达外，观察到PPAR-α蛋白水平随着颈动脉斑块不稳定性增加而呈梯度下降（P<0.001），而AMPK磷酸化增加（P<0.05）。我们的斑块不稳定性体外模型，即用人乙酰化低密度脂蛋白处理人THP-1（Tamm-Horsfall蛋白1）巨噬细胞诱导泡沫细胞形成，支持了我们的体内研究结论。
在不稳定斑块中观察到脂联素总体丰度增加，而AdipoR2表达和活性降低，提示通过AdipoR2通路而非AdipoR1通路的信号传导减少可能导致斑块不稳定。
