Hypothermic protection of the ischemic heart via alterations in apoptotic pathways as assessed by gene array analysis.
Hypothermia improves resistance to ischemia in the cardioplegia-arrested heart. This adaptive process produces changes in specific signaling pathways for mitochondrial proteins and heat-shock response. To further test for hypothermic modulation of other signaling pathways such as apoptosis, we used various molecular techniques, including cDNA arrays. Isolated rabbit hearts were perfused and exposed to ischemic cardioplegic arrest for 2 h at 34 degrees C [ischemic group (I); n = 13] or at 30 degrees C before and during ischemia [hypothermic group (H); n = 12]. Developed pressure, the maximum first derivative of left ventricular pressure, oxygen consumption, and pressure-rate product (P < 0.05) recovery were superior in H compared with in I during reperfusion. mRNA expression for the mitochondrial proteins, adenine translocase and the beta-subunit of F1-ATPase, was preserved by hypothermia. cDNA arrays revealed that ischemia altered expression of 13 genes. Hypothermia modified this response to ischemia for eight genes, six related to apoptosis. A marked, near fivefold increase in transformation-related protein 53 in I was virtually abrogated in H. Hypothermia also increased expression for the anti-apoptotic Bcl-2 homologue Bcl-x relative to I but decreased expression for the proapoptotic Bcl-2 homologue bak. These data imply that hypothermia modifies signaling pathways for apoptosis and suggest possible mechanisms for hypothermia-induced myocardial protection.
Ning
Xue-Han
XH
Division of Cardiology, Department of Pediatrics, University of Washington, Seattle 98195, USA. xh@u.washington.edu
Chen
Shi-Han
SH
Xu
Cheng-Su
CS
Li
Linheng
L
Yao
Lena Y
LY
Qian
Kun
K
Krueger
Julia J
JJ
Hyyti
Outi M
OM
Portman
Michael A
MA
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015152:Blotting, Northern; D001833:Body Temperature Regulation / Q000502:physiology; D005260:Female; D006321:Heart / Q000503:physiopathology*; D006324:Heart Arrest, Induced / Q000379:methods*; D007036:Hypothermia, Induced; D066298:In Vitro Techniques; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D000226:Mitochondrial ADP, ATP Translocases / Q000235:genetics / Q000378:metabolism; D017202:Myocardial Ischemia / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010101:Oxygen Consumption; D011312:Pressure; D021122:Protein Subunits; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D006180:Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D016277:Ventricular Function, Left; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein
D008565:Membrane Proteins; D021122:Protein Subunits; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein; D000226:Mitochondrial ADP, ATP Translocases; D006180:Proton-Translocating ATPases