Exploring the protective effects of schizandrol A in acute myocardial ischemia mice by comprehensive metabolomics profiling integrated with molecular mechanism studies.,Acta Pharmacologica Sinica

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Exploring the protective effects of schizandrol A in acute myocardial ischemia mice by comprehensive metabolomics profiling integrated with molecular mechanism studies.
Acta Pharmacologica Sinica ( IF 6.9 ) Pub Date : 2020-03-02 , DOI: 10.1038/s41401-020-0377-7
Qiong Lai ₁ , Guang-Ying Yuan ₁ , Hao Wang ₂ , Ze-Liang Liu ₁ , Jun-Ping Kou ₁ , Bo-Yang Yu ₁ , Fang Li ₁

Affiliation

Schizandrol A (SA) is an bioactive component isolated from the Schisandra chinensis (Turcz.) Baill., which has been used as a remedy to prevent oxidative injury. However, whether the cardioprotective effect of SA is associated with regulating endogenous metabolites remains unclear, thus we performed comprehensive metabolomics profiling in acute myocardial ischemia (AMI) mice following SA treatment. AMI was induced in ICR mice by coronary artery ligation, then SA (6 mg·kg-1·d-1, ip) was administered. SA treatment significantly decreased the infarct size, preserved the cardiac function, and improved the biochemical indicators and cardiac pathological alterations. Moreover, SA (10, 100 M) significantly decreased the apoptotic index in OGD-treated H8c2 cardiomycytes in vitro. By using HPLC-Q-TOF/MS, we conducted metabonomics analysis to screen the significantly changed endogenous metabolites and construct the network in both serum and urine. The results revealed that SA regulated the pathways of glycine, serine and threonine metabolism, lysine biosynthesis, pyrimidine metabolism, arginine and proline metabolism, cysteine and methionine metabolism, valine, leucine and isoleucine biosynthesis under the pathological conditions of AMI. Furthermore, we selected the regulatory enzymes related to heart disease, including ecto-5'-nucleotidase (NT5E), guanidinoacetate N-methyltransferase (GAMT), platelet-derived endothelial cell growth factor (PD-ECGF) and methionine synthase (MTR), for validation. In addition, SA was found to facilitate PI3K/Akt activation and inhibit the expression of NOX2 in AMI mice and OGD-treated H9c2 cells. In conclusion, we have elucidated SA-regulated endogenous metabolic pathways and constructed a regulatory metabolic network map. Furthermore, we have validated the new potential therapeutic targets and underlying molecular mechanisms of SA against AMI, which might provide a reference for its future application in cardiovascular diseases.

中文翻译：

通过综合代谢组学分析与分子机制研究相结合，探讨五味子醇 A 对急性心肌缺血小鼠的保护作用。

五味子醇 A (SA) 是从五味子 (Turcz.) Baill. 中分离出来的生物活性成分，已被用作预防氧化损伤的药物。然而，SA 的心脏保护作用是否与调节内源代谢物有关仍不清楚，因此我们对 SA 治疗后的急性心肌缺血 (AMI) 小鼠进行了全面的代谢组学分析。通过结扎冠状动脉在ICR小鼠中诱导AMI，然后给予SA（6 mg·kg-1·d-1，ip）。 SA治疗显着减少了梗塞面积，保留了心功能，并改善了生化指标和心脏病理改变。此外，SA (10, 100 M) 显着降低体外 OGD 处理的 H8c2 心肌细胞的凋亡指数。通过使用HPLC-Q-TOF/MS，我们进行了代谢组学分析，筛选了血清和尿液中发生显着变化的内源代谢物并构建了网络。结果表明，在AMI病理条件下，SA调节甘氨酸、丝氨酸和苏氨酸代谢、赖氨酸生物合成、嘧啶代谢、精氨酸和脯氨酸代谢、半胱氨酸和蛋氨酸代谢、缬氨酸、亮氨酸和异亮氨酸生物合成途径。此外，我们还选择了与心脏病相关的调节酶，包括外切5'-核苷酸酶（NT5E）、胍基乙酸N-甲基转移酶（GAMT）、血小板源性内皮细胞生长因子（PD-ECGF）和蛋氨酸合酶（MTR），用于验证。此外，在 AMI 小鼠和 OGD 处理的 H9c2 细胞中，SA 可促进 PI3K/Akt 激活并抑制 NOX2 的表达。总之，我们阐明了SA调节的内源代谢途径并构建了调节代谢网络图。此外，我们还验证了SA抗AMI的新的潜在治疗靶点和潜在分子机制，这可能为其未来在心血管疾病中的应用提供参考。

更新日期：2020-04-24

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