Lin Kuan-Ho, Kuo Wei-Wen, Jiang Ai-Zhi, Pai Peiying, Lin Jing-Ying, Chen Wei-Kung, Day Cecilia Hsuan, Shen Chia-Yao, Padma V Vijaya, Huang Chih Yang
Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
Cell Physiol Biochem. 2015;36(1):334-44. doi: 10.1159/000374076. Epub 2015 May 5.
Hemorrhagic shock (HS) is the major cause of death from trauma. Hemorrhagic shock may lead to cellular hypoxia and organ damage. Our previous findings showed that HS induced a cardiac apoptosis pathway and synergistically caused myocardial cell damage in diabetic rats under trauma-induced HS. Tetramethylpyrazine (TMP) is a major biologically active ingredient purified from the rhizome of Ligusticum wallichii (called Chuang Xiong in Chinese). Chuan Xiong rescued cells from synergistic cardiomyoblast cell injury under high-glucose (HG) conditions plus hypoxia. TMP is one of the most important active ingredients that elevated the survival rate in ischemic brain injury and prevented inducible NO synthase expression to have anti-inflammatory effects against cell damage in different cell types.
Here, we further investigate whether TMP can protect against hypoxic (<1% oxygen) conditions in H9c2 cardiomyoblast cells for 24 hrs.
Our results showed that hypoxia mediated through HIF-1α/JNK/p38 activation significantly elevated the levels of the hypoxia-related proteins HIF-1α, BNIP3 and IGFBP3, further enhanced the pro-apoptotic protein Bak and upregulated downstream Caspase 9 and 3, resulting in cell death. All of these phenomena were fully recovered under TMP treatment. We observed that TMP exerted this effect by activating the IGF1 receptor survival pathway, dependent primarily on PI3K/Akt. When PI3K (class I) was blocked by specific siRNA, the hypoxia-induced activated caspase 3 and cell apoptosis could not be reversed by TMP treatment.
Our results strongly suggest that TMP could be used to restore hypoxia-induced myocardial cell apoptosis and cardiac hypoxic damage.
失血性休克（HS）是创伤致死的主要原因。失血性休克可能导致细胞缺氧和器官损伤。我们之前的研究结果表明，在创伤性失血性休克的糖尿病大鼠中，失血性休克诱导了心脏凋亡途径并协同导致心肌细胞损伤。川芎嗪（TMP）是从川芎根茎中纯化得到的主要生物活性成分（中文称为川芎）。川芎在高糖（HG）条件加缺氧的情况下挽救细胞免受协同的心肌母细胞损伤。川芎嗪是提高缺血性脑损伤存活率并阻止诱导型一氧化氮合酶表达以对不同细胞类型的细胞损伤产生抗炎作用的最重要活性成分之一。
在此，我们进一步研究川芎嗪是否能保护H9c2心肌母细胞免受24小时低氧（氧气<1%）条件的影响。
我们的结果表明，通过HIF-1α/JNK/p38激活介导的缺氧显著提高了缺氧相关蛋白HIF-1α、BNIP3和IGFBP3的水平，进一步增强了促凋亡蛋白Bak并上调了下游的半胱天冬酶9和3，导致细胞死亡。在川芎嗪处理下，所有这些现象都完全恢复。我们观察到川芎嗪通过激活IGF1受体存活途径发挥这种作用，主要依赖于PI3K/Akt。当PI3K（I类）被特异性siRNA阻断时，川芎嗪处理无法逆转缺氧诱导的激活的半胱天冬酶3和细胞凋亡。
我们的结果强烈表明，川芎嗪可用于恢复缺氧诱导的心肌细胞凋亡和心脏缺氧损伤。
