Mitochondria are targets for geranylgeranylacetone-induced cardioprotection against ischemia-reperfusion in the rat heart.

Abstract

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.

• Authors: Tetsuji Shinohara, Naohiko Takahashi, Hiroaki Kohno, Kunitoshi Yamanaka, Tatsuhiko Ooie, Osamu Wakisaka, Yukichi Murozono, Yayoi Taniguchi, Yasuko Torigoe, Masahide Hara, Tatsuo Shimada, Tetsunori Saikawa, Hironobu Yoshimatsu
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 293 Issue 3 Pg. H1892-9 (Sep 2007) ISSN: 0363-6135 [Print] United States
• PMID: 17586615 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Arrhythmia Agents
• Anti-Ulcer Agents
• Decanoic Acids
• Diterpenes
• HSP72 Heat-Shock Proteins
• Hydroxy Acids
• Potassium Channels
• RNA, Small Interfering
• mitochondrial K(ATP) channel
• 5-hydroxydecanoic acid
• Creatine Kinase, MB Form
• geranylgeranylacetone
• Glyburide

Topics

• Animals
• Anti-Arrhythmia Agents (pharmacology)
• Anti-Ulcer Agents (pharmacology, therapeutic use)
• Cell Respiration (drug effects, physiology)
• Cells, Cultured
• Creatine Kinase, MB Form (metabolism)
• Decanoic Acids (pharmacology)
• Diterpenes (pharmacology, therapeutic use)
• Gene Expression Regulation (drug effects)
• Glyburide (pharmacology)
• HSP72 Heat-Shock Proteins (genetics, metabolism)
• Hydroxy Acids (pharmacology)
• Male
• Mitochondria, Heart (drug effects, metabolism, ultrastructure)
• Myocardial Reperfusion Injury (metabolism, prevention & control)
• Myocardium (metabolism, pathology)
• Myocytes, Cardiac (drug effects, metabolism, pathology)
• Potassium Channels (physiology)
• RNA, Small Interfering (pharmacology)
• Rats
• Rats, Sprague-Dawley