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隐丹参酮通过靶向 Akt-GSK-3β-mPTP 通路减轻阿霉素诱导的心肌细胞毒性。

Cryptotanshinone Ameliorates Doxorubicin-Induced Cardiotoxicity by Targeting Akt-GSK-3β-mPTP Pathway In Vitro.

机构信息

School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.

Beijing Key Laboratory of TCM Syndrome and Formula, Beijing 100029, China.

出版信息

Molecules. 2021 Mar 8;26(5):1460. doi: 10.3390/molecules26051460.

DOI:10.3390/molecules26051460
PMID:33800264
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7962658/
Abstract

Cardiotoxicity is one of the main side effects of doxorubicin (Dox) treatment. Dox could induce oxidative stress, leading to an opening of the mitochondrial permeability transition pore (mPTP) and apoptosis in cardiomyocytes. Previous studies have shown that Cryptotanshinone (Cts) has potential cardioprotective effects, but its role in Dox-induced cardiotoxicity (DIC) remains unknown. A Dox-stimulated H9C2 cell model was established. The effects of Cts on cell viability, reactive oxygen species (ROS), superoxide ion accumulation, apoptosis and mitochondrial membrane potential (MMP) were evaluated. Expressions of proteins in Akt-GSK-3β pathway were detected by Western blot. An Akt inhibitor was applied to investigate the effects of Cts on the Akt-GSK-3β pathway. The effects of Cts on the binding of p-GSK-3β to ANT and the formation of the ANT-CypD complex were explored by immunoprecipitation assay. The results showed that Cts could increase cell viability, reduce ROS levels, inhibit apoptosis and protect mitochondrial membrane integrity. Cts increased phosphorylated levels of Akt and GSK-3β. After cells were co-treated with an Akt inhibitor, the effects of Cts were abolished. An immunoprecipitation assay showed that Cts significantly increased GSK-3β-ANT interaction and attenuated Dox-induced formation of the ANT-CypD complex, thereby inhibiting opening of the mPTP. In conclusion, Cts could ameliorate oxidative stress and apoptosis via the Akt-GSK-3β-mPTP pathway.

摘要

心脏毒性是多柔比星（Dox）治疗的主要副作用之一。Dox 可诱导氧化应激，导致心肌细胞中线粒体通透性转换孔（mPTP）开放和细胞凋亡。先前的研究表明，隐丹参酮（Cts）具有潜在的心脏保护作用，但它在 Dox 诱导的心脏毒性（DIC）中的作用尚不清楚。建立了 Dox 刺激的 H9C2 细胞模型。评估了 Cts 对细胞活力、活性氧（ROS）、超氧阴离子积累、细胞凋亡和线粒体膜电位（MMP）的影响。通过 Western blot 检测 Akt-GSK-3β通路中蛋白质的表达。应用 Akt 抑制剂研究 Cts 对 Akt-GSK-3β 通路的影响。通过免疫沉淀测定探讨了 Cts 对 p-GSK-3β 与 ANT 结合和 ANT-CypD 复合物形成的影响。结果表明，Cts 可增加细胞活力，降低 ROS 水平，抑制细胞凋亡，保护线粒体膜完整性。Cts 增加了 Akt 和 GSK-3β 的磷酸化水平。当细胞与 Akt 抑制剂共同处理时，Cts 的作用被消除。免疫沉淀测定表明，Cts 显著增加了 GSK-3β-ANT 相互作用，并抑制了 Dox 诱导的 ANT-CypD 复合物形成，从而抑制了 mPTP 的开放。总之，Cts 可通过 Akt-GSK-3β-mPTP 通路改善氧化应激和细胞凋亡。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1f7/7962658/7ef06b5b8396/molecules-26-01460-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1f7/7962658/a23152e4e817/molecules-26-01460-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1f7/7962658/65c817d17f78/molecules-26-01460-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1f7/7962658/0d0909643ff6/molecules-26-01460-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1f7/7962658/41398357d0be/molecules-26-01460-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1f7/7962658/0bc2c230f2c6/molecules-26-01460-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1f7/7962658/7ef06b5b8396/molecules-26-01460-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1f7/7962658/a23152e4e817/molecules-26-01460-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1f7/7962658/65c817d17f78/molecules-26-01460-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1f7/7962658/0d0909643ff6/molecules-26-01460-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1f7/7962658/41398357d0be/molecules-26-01460-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1f7/7962658/0bc2c230f2c6/molecules-26-01460-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1f7/7962658/7ef06b5b8396/molecules-26-01460-g006.jpg

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