College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China.
College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, PR China.
Toxicology. 2021 Apr 15;453:152733. doi: 10.1016/j.tox.2021.152733. Epub 2021 Feb 21.
Cadmium (Cd) is one common environmental pollutant with systemic toxicity. Lipoxin A4 (LXA4) can regulate transforming growth factor-β (TGF-β) pathway and alleviate tissue injury via binding to formyl peptide receptor 2 (FPR2). The activation of nuclear factor-κB (NF-κB) pathway can promote the occurence of necroptosis. However, whether Cd exposure induces necroptosis in swine myocardium and the role of FPR2/TGF-β/NF-κB pathway in this process are unclear. Hence, we established Cd-exposed swine myocardial injury model by feeding a CdCl added diet (20 mg Cd/kg diet). Hematoxylin-eosin (H&E) staining was used to observe the morphological changes, and inductively coupled plasma mass spectrometry (ICP-MS) was performed to detect the levels of ion elements in myocardium. We further detected LXA4 and its receptor FPR2, TGF-β, Nrf2, NF-κB pathway and necroptosis related-genes expressions by RT-PCR and western blot. The results showed that Cd exposure induced necrotic cell death and ion homeostasis imbalance in swine myocardium. Moreover, Cd exposure increased the LXA4 content, inhibited the FPR2 expression, activated TGF-β pathway and suppressed Nrf2 pathway, activating the NF-κB pathway. In addition, Cd exposure increased the expressions of necroptosis related-genes TNF-α, TNFR1, RIP1, RIP3 and MLKL. It indicated Cd exposure induced necroptosis via FPR2/TGF-β/NF-κB pathway, revealing the potential mechanism of Cd-induced cardiotoxicity in swine myocardium.
镉（Cd）是一种常见的环境污染物，具有全身毒性。脂氧素 A4（LXA4）可以通过与形式肽受体 2（FPR2）结合来调节转化生长因子-β（TGF-β）途径并减轻组织损伤。核因子-κB（NF-κB）途径的激活可以促进坏死性凋亡的发生。然而，Cd 暴露是否会导致猪心肌发生坏死性凋亡以及 FPR2/TGF-β/NF-κB 途径在该过程中的作用尚不清楚。因此，我们通过添加 CdCl 的饮食（20mg Cd/kg 饮食）建立了 Cd 暴露的猪心肌损伤模型。苏木精-伊红（H&E）染色用于观察形态变化，电感耦合等离子体质谱（ICP-MS）用于检测心肌中离子元素的水平。我们进一步通过 RT-PCR 和 Western blot 检测 LXA4 及其受体 FPR2、TGF-β、Nrf2、NF-κB 途径和坏死性凋亡相关基因的表达。结果表明，Cd 暴露诱导猪心肌发生坏死性细胞死亡和离子平衡失调。此外，Cd 暴露增加了 LXA4 含量，抑制了 FPR2 的表达，激活了 TGF-β 途径并抑制了 Nrf2 途径，激活了 NF-κB 途径。此外，Cd 暴露增加了坏死性凋亡相关基因 TNF-α、TNFR1、RIP1、RIP3 和 MLKL 的表达。这表明 Cd 暴露通过 FPR2/TGF-β/NF-κB 途径诱导坏死性凋亡，揭示了 Cd 诱导猪心肌毒性的潜在机制。
