title: Tetramethylpyrazine Ameliorated Hypoxia-Induced Myocardial Cell Apoptosis via HIF-1α/JNK/p38 and IGFBP3/BNIP3 Inhibition to Upregulate PI3K/Akt Survival Signaling.
abstract: BACKGROUND
  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.
  
  
  METHODS
  Here, we further investigate whether TMP can protect against hypoxic (<1% oxygen) conditions in H9c2 cardiomyoblast cells for 24 hrs.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Our results strongly suggest that TMP could be used to restore hypoxia-induced myocardial cell apoptosis and cardiac hypoxic damage.
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Kuan-Ho
authors.initials: KH
authors.lastname: Lin
authors.forename: Wei-Wen
authors.initials: WW
authors.lastname: Kuo
authors.forename: Ai-Zhi
authors.initials: AZ
authors.lastname: Jiang
authors.forename: Peiying
authors.initials: P
authors.lastname: Pai
authors.forename: Jing-Ying
authors.initials: JY
authors.lastname: Lin
authors.forename: Wei-Kung
authors.initials: WK
authors.lastname: Chen
authors.forename: Cecilia Hsuan
authors.initials: CH
authors.lastname: Day
authors.forename: Chia-Yao
authors.initials: CY
authors.lastname: Shen
authors.forename: V Vijaya
authors.initials: VV
authors.lastname: Padma
authors.forename: Chih Yang
authors.initials: CY
authors.lastname: Huang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D002470:Cell Survival; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects*; D032386:Myoblasts, Cardiac / Q000187:drug effects* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D011719:Pyrazines; C017953:tetramethylpyrazine