冠状动脉疾病患者不同血管周围脂肪组织中脑源性神经营养因子的表达和信号传导,Journal of the American Heart Association

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冠状动脉疾病患者不同血管周围脂肪组织中脑源性神经营养因子的表达和信号传导
Journal of the American Heart Association ( IF 5.0 ) Pub Date : 2021-03-05 , DOI: 10.1161/jaha.120.018322
Sarah Zierold ₁ , Katja Buschmann ₂ , Sogol Gachkar ₁ , Magdalena L Bochenek _{1,

3} , David Velmeden ₁ , Lukas Hobohm _{1,

3} , Christian-Friedrich Vahl ₂ , Katrin Schäfer ₁

Affiliation

背景脑源性神经营养因子 (BDNF) 在神经元和非神经元细胞中表达，可能通过其受体原肌球蛋白相关激酶 B (TrkB) 影响血管功能。在这项研究中，我们确定了 BDNF 在确诊冠状动脉粥样硬化患者的不同血管周围脂肪组织 (PVAT) 库中的表达。 ‐PVAT) 来自 24 名患者（79% 男性；平均年龄，71.7±9.7 岁；中位体重指数，27.4±4.8 kg/m ²) 冠状动脉粥样硬化接受择期冠状动脉搭桥手术。与 IMA-PVAT 相比，C-PVAT 中的 BDNF 蛋白水平显着更高，这与肥胖、代谢综合征或炎症的全身生物标志物无关。与 IMA 相比，主动脉中 BDNF 受体 TrkB 的 mRNA 转录物显着减少。血管壁 TrkB 免疫信号与表达平滑肌细胞标志物的细胞共定位，共聚焦显微镜和流式细胞术证实了人主动脉平滑肌细胞中的 BDNF 受体表达。在 C-PVAT 中也观察到蛋白酪氨酸磷酸酶 1B 水平显着升高，这是大脑中 TrkB 信号传导的负调节因子。在体外，蛋白质酪氨酸磷酸酶 1B 的抑制减弱了 BDNF 对平滑肌细胞增殖、迁移、分化、和胶原蛋白的产生，可能是通过上调低亲和力 p75 神经营养因子受体。神经生长因子或其受体原肌球蛋白相关激酶 A 的表达在 C-PVAT 和 IMA-PVAT 之间没有差异。冠状动脉粥样硬化患者的BDNF信号减少或丢失。

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Brain‐Derived Neurotrophic Factor Expression and Signaling in Different Perivascular Adipose Tissue Depots of Patients With Coronary Artery Disease

BackgroundBrain‐derived neurotrophic factor (BDNF) is expressed in neuronal and nonneuronal cells and may affect vascular functions via its receptor, tropomyosin‐related kinase B (TrkB). In this study, we determined the expression of BDNF in different perivascular adipose tissue (PVAT) depots of patients with established coronary atherosclerosis.Methods and ResultsSerum, vascular tissue, and PVAT surrounding the proximal aorta (C‐PVAT) or internal mammary artery (IMA‐PVAT) was obtained from 24 patients (79% men; mean age, 71.7±9.7 years; median body mass index, 27.4±4.8 kg/m²) with coronary atherosclerosis undergoing elective coronary artery bypass surgery. BDNF protein levels were significantly higher in C‐PVAT compared with IMA‐PVAT, independent of obesity, metabolic syndrome, or systemic biomarkers of inflammation. mRNA transcripts of TrkB, the BDNF receptor, were significantly reduced in aorta compared with IMA. Vessel wall TrkB immunosignals colocalized with cells expressing smooth muscle cell markers, and confocal microscopy and flow cytometry confirmed BDNF receptor expression in human aortic smooth muscle cells. Significantly elevated levels of protein tyrosine phosphatase 1B, a negative regulator of TrkB signaling in the brain, were also observed in C‐PVAT. In vitro, inhibition of protein tyrosine phosphatase 1B blunted the effects of BDNF on smooth muscle cell proliferation, migration, differentiation, and collagen production, possibly by upregulation of low‐affinity p75 neurotrophin receptors. Expression of nerve growth factor or its receptor tropomyosin‐related kinase A did not differ between C‐PVAT and IMA‐PVAT.ConclusionsElevated expression of BDNF in parallel with local upregulation of negative regulators of neurotrophin signaling in perivascular fat and lower TrkB expression suggest that vascular BDNF signaling is reduced or lost in patients with coronary atherosclerosis.

更新日期：2021-03-16

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