The phosphatidylinositol 3-kinase-Akt pathway protects cardiomyocytes from ischaemic and hypoxic apoptosis via mitochondrial function

被引:14
|
作者
Song, Hua-Pei [1 ]
Zhang, Lei [2 ]
Dang, Yong-Ming [1 ]
Yan, Hong [1 ]
Chu, Zhi-Gang [1 ]
Huang, Yue-Sheng [1 ]
机构
[1] Third Mil Med Univ, South West Hosp, State Key Lab Trauma Burn & Combined Injury, Inst Burn Res, Chongqing 400038, Peoples R China
[2] Third Mil Med Univ, Dept Occupat Hlth, Chongqing 400038, Peoples R China
基金
中国国家自然科学基金;
关键词
Bax; calcium overload; cardiomyocyte; caspase; 3; insulin-like growth factor-1; LY294002; mitochondria; p53; phosphatidylinositol; 3-kinase; Akt; PERMEABILITY TRANSITION; INHIBITOR LY294002; CASPASE-3; ACTIVATION; CARDIAC MYOCYTES; CELL-DEATH; BAX; P53; INVOLVEMENT; IGF-1;
D O I
10.1111/j.1440-1681.2010.05355.x
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
P>1. After a severe burn, a marked decrease in myocardial blood flow results in ischaemic and hypoxic injury, which subsequently leads to apoptosis or necrosis. Phosphatidylinositol 3-kinase (PI3-K)/Akt is an important intracellular signal transduction molecule that regulates cell proliferation, differentiation, glucose metabolism and migration. However, the function and mechanisms of the PI3-K-Akt pathway in cardiomyocyte apoptosis after a burn remain unclear. 2. In the present study, an in vivo rat model of burn injury and an in vitro hypoxic model using rat cardiomyocytes were established. In burned rats, the expression of PI3-K and phosphorylated (p-) Akt expression increased, as did myocardial apoptosis. Inhibition of the PI3-K-Akt pathway with 1.4 mg/kg LY294002 caused a significant increase in the myocardial apoptotic index compared with hypoxia alone in the in vivo model. 3. Cardiomyocytes cultured under hypoxic conditions exhibited increased apoptosis, decreased cell viability, enhanced caspase 3 activity, a decreased mitochondrial membrane potential, increased cytoplasmic calcium transients and increased p53 and Bax mRNA expression. Pretreatment with 50 mu mol/L LY294002 significantly enhanced all these negative indicators compared with hypoxia alone. In contrast, pretreatment of cells with 200 ng/mL insulin-like growth factor-1, an activator of PI3-K-Akt, significantly ameliorated the effects of hypoxia, although control levels were not reached. 4. These findings indicate that activation of the PI3-K-Akt pathway induced by ischaemia and hypoxia after a severe burn can protect cardiomyocytes from apoptosis. This anti-apoptotic effect is most likely mediated via the mitochondria and changes in p53 and Bax gene expression, intracellular [Ca2+] and caspase 3 activity.
引用
收藏
页码:598 / 604
页数:7
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