Tian Geer, Zhou Junteng, Quan Yue, Kong Qihang, Wu Wenchao, Liu Xiaojing
Laboratory of Cardiovascular Diseases, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China.
Department of Cardiology, West China Hospital, Sichuan University, Chengdu, China.
Front Pharmacol. 2021 Feb 17;12:627773. doi: 10.3389/fphar.2021.627773. eCollection 2021.
Cardiac fibroblasts (CFs) activation is a hallmark feature of cardiac fibrosis caused by cardiac remodeling. The purinergic signaling molecules have been proven to participate in the activation of CFs. In this study, we explored the expression pattern of P2Y receptor family in the cardiac fibrosis mice model induced by the transverse aortic constriction (TAC) operation and in the activation of CFs triggered by transforming growth factor β1 (TGF-β1) stimulation. We then investigated the role of P2Y1receptor (P2Y1R) in activated CFs. The results showed that among P2Y family members, only P2Y1R was downregulated in the heart tissues of TAC mice. Consistent with our results, the level of P2Y1R was decreased in the activated CFs, when CFs were treated with TGF-β1. Silencing P2Y1R expression with siP2Y1R accelerated the effects of TGF-β1 on CFs activation. Moreover, the P2Y1R selective antagonist BPTU increased the levels of mRNA and protein of profibrogenic markers, such as connective tissue growth factor (CTGF), periostin (POSTN). periostin (POSTN), and α-smooth muscle actin(α-SMA). Further, MRS2365, the agonist of P2Y1R, ameliorated the activation of CFs and activated the p38 MAPK and ERK signaling pathways. In conclusion , our findings revealed that upregulating of P2Y1R may attenuate the abnormal activation of CFs via the p38 MAPK and ERK signaling pathway.
心脏成纤维细胞（CFs）的激活是心脏重塑所致心脏纤维化的一个标志性特征。嘌呤能信号分子已被证明参与CFs的激活。在本研究中，我们探究了P2Y受体家族在经主动脉缩窄（TAC）手术诱导的心脏纤维化小鼠模型中以及在转化生长因子β1（TGF-β1）刺激引发的CFs激活中的表达模式。然后，我们研究了P2Y1受体（P2Y1R）在激活的CFs中的作用。结果显示，在P2Y家族成员中，只有P2Y1R在TAC小鼠的心脏组织中表达下调。与我们的结果一致，当用TGF-β1处理CFs时，激活的CFs中P2Y1R的水平降低。用siP2Y1R沉默P2Y1R表达加速了TGF-β1对CFs激活的作用。此外，P2Y1R选择性拮抗剂BPTU增加了促纤维化标志物的mRNA和蛋白质水平，如结缔组织生长因子（CTGF）、骨膜蛋白（POSTN）、骨膜蛋白（POSTN）和α平滑肌肌动蛋白（α-SMA）。此外，P2Y1R激动剂MRS2365改善了CFs的激活，并激活了p38丝裂原活化蛋白激酶（MAPK）和细胞外信号调节激酶（ERK）信号通路。总之，我们的研究结果表明，上调P2Y1R可能通过p38 MAPK和ERK信号通路减弱CFs的异常激活。
