Piperine protects against pyroptosis in myocardial ischaemia/reperfusion injury by regulating the miR-383/RP105/AKT signalling pathway.
Piperine protects against pyroptosis in myocardial ischaemia/reperfusion injury by regulating the miR-383/RP105/AKT signalling pathway.
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胡椒碱通过调节 miR-383/RP105/AKT 信号通路预防心肌缺血/再灌注损伤中的细胞焦亡
DOI：
10.1111/jcmm.15953
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发表时间：
2021-01
影响因子：
5.3
通讯作者：
Chen MH
中科院分区：
文献类型：
--
作者：
Guo X;Hu S;Liu JJ;Huang L;Zhong P;Fan ZX;Ye P;Chen MH
MiRNA介导的下垂在心肌缺血/再灌注损伤(MIRI)的发生发展中起重要作用。胡椒碱(Piperine，PIP)具有多种药理作用，尤其是在I/R条件下。本研究的重点是PIP是否通过miR-383依赖的途径保护MIRI免受上睑下垂的影响。结扎大鼠左前降支30min，再灌注4h，建立大鼠MIRI模型。检测心肌酶、组织形态、结构和功能以评价MIRI。分别构建了miR-383过表达、miR-383沉默和RP105基因敲除的重组腺病毒载体。使用荧光素酶报告分析确认RP105为miR-383的靶标。Western blotting法检测上睑下垂相关标志物。结果表明，I/R引起心肌损伤，表现为LDH/CK释放增加，心肌梗死面积增加，心肌细胞凋亡率增加，心肌功能和结构恶化。上睑下垂相关介质包括NLRP3、裂解半胱氨酸蛋白酶-1、裂解IL-1β和IL-18也在缺血再灌注后增强。然而，PIP治疗大大改善了MIRI，同时也抑制了焦磷脂的抑制。在机制研究中，PIP可逆转MIRI引起的miR-383的升高和RP105/PI3K/AKT通路的降低。荧光素酶报告实验证实RP105是miR-383的靶点。MiR-383基因敲除虽有改善作用，但miR-383过表达促进了下垂和MIRI的发生。此外，miR-383沉默的抗嗜热作用依赖于RP105/PI3K/AKT信号通路。此外，我们目前的研究进一步表明，PIP治疗MIRI中的下垂是通过miR-383/RP105/AKT依赖的途径进行的。因此，PIP治疗可通过调节miR-383/RP105/AKT通路减轻MIRI和下垂，为MIRI的治疗提供了新的途径。
miRNA‐mediated pyroptosis play crucial effects in the development of myocardial ischaemia/reperfusion (I/R) injury (MIRI). Piperine (PIP) possesses multiple pharmacological effects especially in I/R condition. This study focuses on whether PIP protects MIRI from pyroptosis via miR‐383‐dependent pathway. Rat MIRI model was established by 30 minutes of LAD ligation and 4 hours of reperfusion. Myocardial enzymes, histomorphology, structure and function were detected to evaluate MIRI. Recombinant adenoviral vectors for miR‐383 overexpression or miR‐383 silencing or RP105 knockdown were constructed, respectively. Luciferase reporter analysis was used to confirm RP105 as a target of miR‐383. Pyroptosis‐related markers were measured by Western blotting assay. The results showed that I/R provoked myocardial injury, as shown by the increases of LDH/CK releases, infarcted areas and apoptosis as well as worsened function and structure. Pyroptosis‐related mediators including NLRP3, cleaved caspase‐1, cleaved IL‐1β and IL‐18 were also reinforced after MIRI. However, PIP treatment greatly ameliorated MIRI in parallel with pyroptotic repression. In mechanistic studies, MIRI‐caused elevation of miR‐383 and decrease of RP105/PI3K/AKT pathway were reverted by PIP treatment. Luciferase reporter assay confirmed RP105 as a miR‐383 target. miR‐383 knockdown ameliorated but miR‐383 overexpression facilitated pyroptosis and MIRI. Moreover, the anti‐pyroptotic effect from miR‐383 silencing was verified to be relied on the RP105/PI3K/AKT signalling pathway. Additionally, our present study further indicated the miR‐383/RP105/AKT‐dependent approach resulting from PIP administration against pyroptosis in MIRI. Therefore, PIP treatment attenuates MIRI and pyroptosis by regulating miR‐383/RP105/AKT pathway, and it may provide a therapeutic manner for the treatment of MIRI.
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