title: The phosphatidylinositol 3-kinase-Akt pathway protects cardiomyocytes from ischaemic and hypoxic apoptosis via mitochondrial function.
abstract: 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 mumol/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 [Ca(2+)] and caspase 3 activity.
authors.affiliation: Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, South-west Hospital, Third Military Medical University, Chongqing 400038, China.
authors.forename: Hua-Pei
authors.initials: HP
authors.lastname: Song
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Yong-Ming
authors.initials: YM
authors.lastname: Dang
authors.forename: Hong
authors.initials: H
authors.lastname: Yan
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Chu
authors.forename: Yue-Sheng
authors.initials: YS
authors.lastname: Huang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D002056:Burns / Q000150:complications* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects / Q000502:physiology*; D009025:Morpholines / Q000494:pharmacology; D017202:Myocardial Ischemia / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
chemical_list: D002118:Calcium; D053148:Caspase 3; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016159:Tumor Suppressor Protein p53; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one