Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, China; Research Department of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, China.
Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, China.
J Ethnopharmacol. 2021 Mar 25;268:113639. doi: 10.1016/j.jep.2020.113639. Epub 2020 Dec 7.
ETHNOPHARMACOLOGICAL RELEVANCE: Panax notoginseng saponins (PNS), the main active ingredients of Panax notoginseng (Burkill) F.H.Chen, have been clinically used for cardiovascular diseases treatment in China as the Traditional Chinese Medicine (TCM) (Duan et al., 2017). Evidence demonstrated that PNS protected cardiomyocytes from myocardial ischemia, but the more underlying molecular mechanisms of the protective effect are still unclear. The aims of this study are to systematically know the function of PNS and discover new roles of PNS in ischemic cardiomyocytes. MATERIALS AND METHODS: To confirm PNS function on ischemic cardiomyopathy, we established in vitro myocardial ischemia model on H9C2 cardiomyocyte line, which was induced by oxygen-glucose depletion (OGD). Then RNA-seq was carried out to systematically analyze global gene expression. This study was aimed to systematically investigate the protective effect and more potential molecular mechanisms of PNS on H9C2 cardiomyocytes in vitro through whole-transcriptome analysis with total RNA sequencing (RNA-Seq). RESULTS: PNS exhibited anti-apoptotic effect in H9C2 cardiomyocytes in OGD-induced myocardial ischemia model. Through RNA-seq, we found that OGD affected expression profiling of many genes, including upregulated and downregulated genes. PNS inhibited cardiomyocyte apoptosis and death through rescuing cell cycle arrest, the DNA double-strand breakage repair process and chromosome segregation. Interestingly, for the canonical signaling pathways regulation, RNA-seq showed PNS could inhibit cardiac hypertrophy, MAPK signaling pathway, and re-activate PI3K/AKT and AMPK signaling pathways. Experimental data also confirmed the PNS could protect cardiomyocytes from OGD-induced apoptosis through activating PI3K/AKT and AMPK signaling pathways. Moreover, RNA-seq demonstrated that the expression levels of many non-coding RNAs, such as miRNAs and lncRNAs, were significantly affected after PNS treatment, suggesting that PNS could protect cardiomyocytes through regulating non-coding RNAs. CONCLUSION: RNA-seq systematically revealed different novel roles of Panax Notoginseng Saponins (PNS) in protecting cardiomyocytes from apoptosis, induced by myocardial ischemia, through rescuing cell cycle arrest and cardiac hypertrophy, re-activating the DNA double-strand breakage repair process, chromosome segregation, PI3K/Akt and AMPK signaling pathways and regulating non-coding RNAs.
民族药理学相关性：三七总皂苷（PNS）是三七（Burkill）F.H.Chen 的主要活性成分，在中国已被临床用于心血管疾病的治疗，作为中药（TCM）（段等，2017）。有证据表明，PNS 可保护心肌细胞免受心肌缺血的影响，但保护作用的潜在分子机制尚不清楚。本研究旨在系统了解 PNS 的功能，并发现 PNS 在缺血性心肌细胞中的新作用。
材料和方法：为了证实 PNS 对缺血性心肌病的作用，我们在 H9C2 心肌细胞系上建立了体外心肌缺血模型，该模型由氧葡萄糖剥夺（OGD）诱导。然后进行 RNA 测序以系统分析全局基因表达。本研究旨在通过全转录组分析（RNA-Seq），用总 RNA 测序系统研究 PNS 对体外 H9C2 心肌细胞的保护作用及更多潜在的分子机制。
结果：PNS 在 OGD 诱导的心肌缺血模型的 H9C2 心肌细胞中表现出抗凋亡作用。通过 RNA 测序，我们发现 OGD 影响了许多基因的表达谱，包括上调和下调的基因。PNS 通过挽救细胞周期停滞、DNA 双链断裂修复过程和染色体分离来抑制心肌细胞凋亡和死亡。有趣的是，对于经典信号通路的调节，RNA-Seq 显示 PNS 可以抑制心脏肥大、MAPK 信号通路，并重新激活 PI3K/AKT 和 AMPK 信号通路。实验数据还证实，PNS 可以通过激活 PI3K/AKT 和 AMPK 信号通路来保护心肌细胞免受 OGD 诱导的凋亡。此外，RNA-Seq 表明，许多非编码 RNA（如 miRNA 和 lncRNA）的表达水平在 PNS 处理后显著受到影响，这表明 PNS 可以通过调节非编码 RNA 来保护心肌细胞。
结论：RNA-Seq 系统地揭示了三七总皂苷（PNS）在通过挽救细胞周期停滞、心脏肥大、重新激活 DNA 双链断裂修复过程、染色体分离、PI3K/Akt 和 AMPK 信号通路以及调节非编码 RNA 来保护心肌细胞免受由心肌缺血引起的凋亡方面的不同新作用。
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