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 (mitoKATP) 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 μM) or glibenclamide (10 μM) 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 mitoKATP channel.

Wereport a case of selenium deficiency in a patient with Crohn's disease on long-term total parenteral nutrition (TPN). She manifested lassitude of the legs, discoloration of the nail beds, and macrocytosis. Since her plasma selenium level was found to be below the measurable level, we diagnosed this case as selenium deficiency. After intravenous administration of sodium selenite, her symptoms were reversed. Careful attention should be paid to selenium deficiency when a patient receives longterm TPN;supplementary administration of selenium via TPNmaybe required because selenium is often not routinely added to TPN formulations. (Internal Medicine 42: 154-157, 2003)

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We recently reported that long-term treatment with pioglitazone restored cardiac Akt phosphorylation in response to hyperthermia (HT) and subsequent cardiac heat-shock protein 72 (HSP72) expression, in heredity insulin resistance rats via improvement of insulin sensitivity. Because adrenomedullin (AM) promotes Akt phosphorylation and attenuates myocardial ischemia/reperfusion injury, we tested the hypothesis that pretreatment with AM before HT could restore depressed Akt activation and cardiac HSP72 expression, thereby enhancing protection against ischemia/reperfusion injury in this model. At 16 wk of age, male insulin-resistant Otsuka Long-Evans Tokushima Fatty (OLETF) rats and control Long-Evans Tokushima Otsuka (LETO) rats were treated with AM (0.05 microg/kg . /min iv) or vehicle for 60 min. Thereafter, HT (43 C for 20 min) or normothermia (NT; 37 C for 20 min) was applied. The heart was isolated 1 and 24 h after HT. 1) Either AM or HT induced myocardial Akt phosphorylation in a phosphatidylinositol 3-kinase-dependent manner, which was augmented by their combination. 2) Akt phosphorylation induced by HT, or a combination of HT and AM, was attenuated in insulin-resistant OLETF rat hearts. 3) The levels of Akt phosphorylation in response to AM and/or HT correlated with reperfusion-induced left ventricular functional recovery and amount of released creatine kinase during reperfusion. 4) AM protected the hearts of OLETF rats and LETO rats. Our results suggest that AM pretreatment could enhance HT-induced myocardial Akt phosphorylation and subsequent HSP72 expression in a phosphatidylinositol 3-kinase-dependent manner, in association with tolerance against ischemia/reperfusion injury. This intervention was effective even in insulin-resistant hearts.

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