• Tetsuji Shinohara, Naohiko Takahashi, Hiroaki Kohno, Kunitoshi Yamanaka, Tatsuhiko Ooie, Osamu Wakisaka, Yukichi Murozono, Yayoi Taniguchi, Yasuko Torigoe, Masahide Hara, Tatsuo Shimada, Tetsunori Saikawa, and Hironobu Yoshimatsu.
• Department of Internal Medicine 1, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama, Oita 879-5593, Japan. shinohar@med.oita-u.ac.jp
• Am. J. Physiol. Heart Circ. Physiol. 2007 Sep 1;293(3):H1892-9.

AbstractIt 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.

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