Mitochondria are targets for geranylgeranylacetone-induced cardioprotection against ischemia-reperfusion in the rat heart.
It has been shown that orally administered geranylgeranylacetone (GGA), an anti-ulcer drug, induces expression of heat shock protein 72 (HSP72) and provides protection against ischemia-reperfusion in rat hearts. The underlying protective mechanisms, however, remain unknown. Mitochondria have been shown to be a selective target for heat stress-induced cardioprotection. Therefore, we hypothesized that preservation of mitochondrial function, owing to an opening of a putative channel in the inner mitochondrial membrane, the mitochondrial ATP-sensitive potassium (mitoK(ATP)) channel, could be involved in GGA- or heat stress-induced cardioprotection against ischemia-reperfusion. Rats were treated with oral GGA or vehicle. Twenty-four hours later, each heart was isolated and perfused with a Langendorff apparatus. GGA-treated hearts showed better functional recovery, and less creatine kinase was released during a 30-min reperfusion period, after 20 min of no-flow ischemia. Concomitant perfusion with 5-hydroxydecanoate (5-HD, 100 microM) or glibenclamide (10 microM) abolished the GGA-induced cardioprotective effect. GGA also showed preserved mitochondrial respiratory function, isolated at the end of the reperfusion period, which was abolished with 5-HD treatment. GGA prevented destruction of the mitochondrial structure by ischemia-reperfusion, as shown by electron microscopy. In cultured cardiomyocytes, GGA induced HSP72 expression and resulted in less damage to cells, including less apoptosis in response to hypoxia-reoxygenation. Treatment with 5-HD abolished the GGA-induced cardioprotective effects but did not affect HSP72 expression. Our results indicate that preserved mitochondrial respiratory function, owing to GGA-induced HSP72 expression, may, at least in part, have a role in cardioprotection against ischemia-reperfusion. These processes may involve opening of the mitoK(ATP) channel.
Shinohara
Tetsuji
T
Department of Internal Medicine 1, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama, Oita 879-5593, Japan. shinohar@med.oita-u.ac.jp
Takahashi
Naohiko
N
Kohno
Hiroaki
H
Yamanaka
Kunitoshi
K
Ooie
Tatsuhiko
T
Wakisaka
Osamu
O
Murozono
Yukichi
Y
Taniguchi
Yayoi
Y
Torigoe
Yasuko
Y
Hara
Masahide
M
Shimada
Tatsuo
T
Saikawa
Tetsunori
T
Yoshimatsu
Hironobu
H
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D000897:Anti-Ulcer Agents / Q000494:pharmacology* / Q000627:therapeutic use; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D052279:Creatine Kinase, MB Form / Q000378:metabolism; D003652:Decanoic Acids / Q000494:pharmacology; D004224:Diterpenes / Q000494:pharmacology* / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects; D005905:Glyburide / Q000494:pharmacology; D050884:HSP72 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006880:Hydroxy Acids / Q000494:pharmacology; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015221:Potassium Channels / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000889:Anti-Arrhythmia Agents; D000897:Anti-Ulcer Agents; D003652:Decanoic Acids; D004224:Diterpenes; D050884:HSP72 Heat-Shock Proteins; D006880:Hydroxy Acids; D015221:Potassium Channels; D034741:RNA, Small Interfering; C117780:mitochondrial K(ATP) channel; C052853:5-hydroxydecanoic acid; D052279:Creatine Kinase, MB Form; C031049:geranylgeranylacetone; D005905:Glyburide