Cannabidiol represses miR-143 to promote cardiomyocyte proliferation and heart regeneration after myocardial infarction.
Cannabidiol represses miR-143 to promote cardiomyocyte proliferation and heart regeneration after myocardial infarction.
复制标题
DOI：
10.1016/j.ejphar.2023.176245
复制
发表时间：
2023-12
影响因子：
5
通讯作者：
Zhongyu Ren;Yi-ning Liu;Ao Cai;Yang Yu;Xiuxiu Wang;Lan lan;Xiaofei Guo;Hong Yan;Xinlu G
中科院分区：
文献类型：
--
作者：
Zhongyu Ren;Yi-ning Liu;Ao Cai;Yang Yu;Xiuxiu Wang;Lan lan;Xiaofei Guo;Hong Yan;Xinlu G
哺乳动物的心脏在出生后的早期就能够通过内源性心肌细胞增殖而几乎完全再生。然而，这种再生能力随着生长而逐渐减弱，并且在成年期几乎丧失。大麻二酚（CBD）是大麻的主要成分，具有调节氧化应激、纤维化、炎症和细胞死亡的各种生物活性。本研究旨在研究CBD对MI后小鼠心脏再生的药理作用。采用冠状动脉结扎法建立成年小鼠心肌梗死模型，并分别给予或不给予CBD。我们的研究结果表明，全身给药（10毫克/公斤）的CBD显着增加心脏再生能力，减少梗死面积，并恢复心肌梗死小鼠的心脏功能。同时，体外研究也表明CBD能够促进乳鼠心肌细胞的增殖。从机制上讲，与心肌细胞增殖相关的miR-143- 3 p的表达在CBD处理的心肌细胞中显著下调，而miR-143- 3 p的过表达抑制心肌细胞有丝分裂并消除CBD诱导的心肌细胞增殖。此外，CBD还能促进miR-143- 3 p靶基因雅普和Ctnnd 1的表达。雅普和Ctnnd 1的沉默阻碍了CBD的增殖作用。我们进一步发现，大麻素受体2的抑制阻碍了CBD对miR-143- 3 p及其下游靶点雅普/Ctnnd 1的调节作用，这最终消除了CBD对新生儿和成人心肌细胞的促增殖作用。综上所述，CBD通过miR-143- 3 p/雅普/Ctnnd 1信号通路促进MI后心肌细胞增殖和心脏再生，为成年心肌的心脏修复提供了新的策略。
Mammalian heart is capable to regenerate almost completely early after birth through endogenous cardiomyocyte proliferation. However, this regenerative capacity diminishes gradually with growth and is nearly lost in adulthood. Cannabidiol (CBD) is a major component of cannabis and has various biological activities to regulate oxidative stress, fibrosis, inflammation, and cell death. The present study was conducted to investigate the pharmacological effects of CBD on heart regeneration in post-MI mice. MI models in adult mice were constructed via coronary artery ligation, which were administrated with or without CBD. Our results demonstrate that systemic administration (10 mg/kg) of CBD markedly increased cardiac regenerative ability, reduced infarct size, and restored cardiac function in MI mice. Consistently,in vitrostudy also showed that CBD was able to promote the proliferation of neonatal cardiomyocytes. Mechanistically, the expression of miR-143–3p related to cardiomyocyte proliferation was significantly down-regulated in CBD-treated cardiomyocytes, while the overexpression of miR-143–3p inhibited cardiomyocyte mitosis and eliminated CBD-induced cardiomyocyte proliferation. Moreover, CBD enhanced the expression of Yap and Ctnnd1, which were demonstrated as the target genes of miR-143–3p. Silencing of Yap and Ctnnd1 hindered the proliferative effects of CBD. We further revealed that inhibition of the cannabinoid receptor 2 impeded the regulatory effect of CBD on miR-143–3p and its downstream target Yap/Ctnnd1, which ultimately eliminated the pro-proliferative effect of CBD on neonatal and adult cardiomyocytes. Taken together, CBD promotes cardiomyocyte proliferation and heart regeneration after MI via miR-143–3p/Yap/Ctnnd1 signaling pathway, which provides a new strategy for cardiac repair in adult myocardium.