Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Oxid Med Cell Longev. 2022 Jul 26;2022:4499219. doi: 10.1155/2022/4499219. eCollection 2022.
Acute pancreatitis (AP) is an inflammatory disease that is associated with trypsinogen activation, mitochondrial dysfunction, cell death, and inflammation. Dopamine D2 receptor (DRD2) plays an essential role in alleviating AP, while it is unclear whether it is involved in regulating acinar cell necroptosis. Here, we found that DRD2 agonist quinpirole alleviated acinar cell necroptosis via inhibiting cathepsin B (CTSB). Moreover, CTSB inhibition by CA-074Me ameliorated AP severity by reducing necroptosis. Notably, knockdown of TFAM reversed the therapeutic effect of either quinpirole or CA-074Me. We identified a new mechanism that DRD2 signaling inhibited CTSB and promoted the expression of mitochondrial transcription factor A(TFAM), leading to reduction of ROS production in AP, which attenuated acinar cell necroptosis ultimately. Collectively, our findings provide new evidence that DRD2 agonist could be a new potential therapeutic strategy for AP treatment.
急性胰腺炎（AP）是一种炎症性疾病，与胰蛋白酶原激活、线粒体功能障碍、细胞死亡和炎症有关。多巴胺 D2 受体（DRD2）在缓解 AP 中起着重要作用，但尚不清楚它是否参与调节腺泡细胞坏死性凋亡。在这里，我们发现 DRD2 激动剂喹吡罗通过抑制组织蛋白酶 B（CTSB）来减轻腺泡细胞坏死性凋亡。此外，通过 CA-074Me 抑制 CTSB 可通过减少坏死性凋亡来改善 AP 的严重程度。值得注意的是，TFAM 的敲低逆转了喹吡罗或 CA-074Me 的治疗效果。我们确定了一种新的机制，即 DRD2 信号抑制 CTSB 并促进线粒体转录因子 A（TFAM）的表达，从而减少 AP 中的 ROS 产生，最终减轻腺泡细胞坏死性凋亡。总之，我们的研究结果为 DRD2 激动剂可能成为治疗 AP 的一种新的潜在治疗策略提供了新的证据。
