IGF-I differentially regulates Bcl-xL and Bax and confers myocardial protection in the rat heart.
Bcl-2 family proteins play a crucial role in the cytoprotective action of insulin-like growth factor-I (IGF-I) by regulating cell death signaling at the mitochondrial level. The present study examined the effect of IGF-I on the expression of Bcl-2 family proteins in the rat heart mitochondria in relation to myocardial protection against ischemia-reperfusion injury. Systemic IGF-I (1 mg) treatment in the rat increased Bcl-xL and attenuated Bax 12-24 h later in the heart mitochondria fraction. Permeability transition and cytochrome c release occurred in a Ca(2+) concentration-dependent manner in the vehicle-treated mitochondria. This was significantly inhibited by the IGF-I-pretreatment. Moreover, ATP synthesis was significantly greater in the IGF-I-pretreated mitochondria. IGF-I pretreatment 24 h before 25 min of global ischemia in the isolated rat heart model significantly improved recovery of isovolumic left ventricular function and inhibited creatine kinase release during reperfusion. This was associated with a significantly less number of terminal transferase labeling-positive myocytes and nonmyocytes 2 h after reperfusion. These results suggest that IGF-1 differentially regulates Bcl-xL and Bax in heart mitochondria, which may be causally related to myocardial protection against ischemia-reperfusion injury.
Yamamura
T
T
Department of Thoracic and Cardiovascular Surgery, Kansai Medical University, Moriguchi, Osaka 570, Japan.
Otani
H
H
Nakao
Y
Y
Hattori
R
R
Osako
M
M
Imamura
H
H
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D002352:Carrier Proteins / Q000032:analysis / Q000378:metabolism; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology; D003576:Electron Transport Complex IV / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D008933:Mitochondrial Swelling / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein
C494821:Bad protein, rat; C494828:Bax protein, rat; C494813:Bcl2l1 protein, rat; D002352:Carrier Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D007334:Insulin-Like Growth Factor I; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV