Department of Cardiology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
Department of Cardiology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
Int J Cardiol. 2024 Dec 1;416:132505. doi: 10.1016/j.ijcard.2024.132505. Epub 2024 Aug 31.
Myocardial ischemia-reperfusion(I/R)injury constitute the fundamental pathophysiology of acute myocardial infarction (AMI). Ischemic heart releases macrophage migration inhibitory factor (MIF), which activates MIF- AMPK signaling pathway. Depression is a significant risk factor for AMI. In a state of depression, peripheral expression of cannabinoid receptor 2 (CNR2) genes was downregulated.
We investigated the mechanism by which depression exacerbates myocardial I/R injury through the CNR2 and MIF-AMPK signaling pathways.
We established mouse models of depression and myocardial I/R. Left ventricular function was assessed using cardiac ultrasound and TTC staining. The protein levels of myocardial CNR2, MIF, AMPK, and ACC were determined by Western blot, while the expression level of CNR2 was measured using RT-qPCR. Additionally, MIF content in peripheral blood was quantified using ELISA.
After I/R, the expression level of CNR2 was found to be lower in the depression group, leading to a deterioration in left heart function. Depressed mice exhibited lower secretion of MIF, accompanied by a decrease in the activation of the MIF-AMPK signaling pathway. However, injection of CNR2 agonist JWH133 prior to ischemia increased the activation of the MIF-AMPK signaling pathway, while CNR2 inhibitor AM630 decreased the activation.
Further research is needed to investigate the specific neuroendocrine mechanism affecting myocardial CNR2 expression in depression. And these experimental conclusions require further verification at the cellular level.
The activation of CNR2 in myocardium following I/R is impeded by depression, thereby exacerbating myocardial I/R injury through attenuation of the MIF-AMPK signaling pathway activation.
心肌缺血再灌注（I/R）损伤构成了急性心肌梗死（AMI）的基本病理生理学。缺血性心脏释放巨噬细胞移动抑制因子（MIF），激活 MIF-AMPK 信号通路。抑郁症是 AMI 的重要危险因素。在抑郁状态下，周围大麻素受体 2（CNR2）基因的表达下调。
我们通过 CNR2 和 MIF-AMPK 信号通路研究了抑郁症加重心肌 I/R 损伤的机制。
我们建立了抑郁和心肌 I/R 的小鼠模型。使用心脏超声和 TTC 染色评估左心室功能。通过 Western blot 测定心肌 CNR2、MIF、AMPK 和 ACC 的蛋白水平，通过 RT-qPCR 测定 CNR2 的表达水平。此外，使用 ELISA 定量测定外周血中的 MIF 含量。
在 I/R 后，发现抑郁组的 CNR2 表达水平较低，导致左心功能恶化。抑郁小鼠表现出较低的 MIF 分泌，同时 MIF-AMPK 信号通路的激活减少。然而，在缺血前注射 CNR2 激动剂 JWH133 会增加 MIF-AMPK 信号通路的激活，而 CNR2 抑制剂 AM630 则会减少其激活。
需要进一步研究影响抑郁症中心肌 CNR2 表达的特定神经内分泌机制。并且这些实验结论需要在细胞水平上进一步验证。
I/R 后心肌中 CNR2 的激活被抑郁症所抑制，从而通过减弱 MIF-AMPK 信号通路的激活来加重心肌 I/R 损伤。
