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preserves function and signaling for mitochondrial biogenesis during subsequent ischemia. Am. J. Physiol. 274 (Heart Circ. Physiol. 43): H786-H793, 1998.-Hypothermia is known to protect myocardium during ischemia, but its role in induction of a protective stress response before ischemia has not been evaluated. As cold incites stress responses in other tissues, including heat shock protein induction and signaling mitochondrial biogenesis, we postulated that hypothermia in perfused hearts would produce similar phenomena while reducing injury during subsequent ischemia. Studies were performed in isolated perfused rabbit hearts (n ϭ 77): a control group (C) and a hypothermic group (H) subjected to decreasing infusate temperature from 37 to 31°C over 20 min. Subsequent ischemia during cardioplegic arrest at 34°C for 120 min was followed by reperfusion. At 15 min of reperfusion, recovery of left ventricular developed pressure (LVDP), maximum first derivative of left ventricular pressure (LV dP/dt max ), LV ϪdP/dt max , and the product of heart rate and LVDP was significantly increased in H (P Ͻ 0.01) compared with C hearts. Ischemic contracture started later in H (97.5 Ϯ 3.6 min) than in C (67.3 Ϯ 3.3 min) hearts. Myocardial ATP preservation and repletion during ischemia and reperfusion were higher in H than in C hearts. mRNA levels of the nuclear-encoded mitochondrial proteins adenine nucleotide translocase isoform 1 (ANT 1 ) and ␤-F 1 -adenosinetriphosphatase (␤-F 1 -ATPase) normalized to 28S RNA decreased in C hearts but were preserved in H hearts after reperfusion. Inducible heat shock protein (HSP70-1) mRNA was elevated nearly 4-fold after ischemia in C hearts and 12-fold in H hearts. These data indicate that hypothermia preserves myocardial function and ATP stores during subsequent ischemia and reperfusion. Signaling for mitochondrial biogenesis indexed by ANT 1 and ␤-F 1 -ATPase mRNA levels is also preserved during a marked increase in HSP70-1 mRNA.adenine nucleotide translocase isoform 1; ␤-F 1 -adenosinetriphosphatase; cold adaptation; inducible heat shock protein; myocardial reperfusion COLD-INDUCED STRESS is a phenomenon associated with an increase in inducible heat shock protein expression in various tissues (31,32). Particularly in brown adipose tissue, cold-induced stress or hypothermia also induces mitochondrial biogenesis (20,29,30). At the transcriptional level this is characterized by coordinated increases in expression of nuclear-and mitochondrial-encoded genes regulating mitochondrial membrane proteins (28). Although this signaling has been well characterized in brown adipose fat, it remains relatively unexplored in other mammalian tissues. This is surprising because stress responses in the heart secondary to heat shock or ischemia have been a major focus of investigation with respect to enhancement of tissue resistance to subsequent ischemia (14,21,33,35,40). Furthermore, hypothermia either singly or accompanied by cardioplegia is regularly employed in myocardial protection during heart surgery. T...

Hypothermia preserves myocardial function, promotes signaling for cell survival, and inhibits apoptotic pathways during 45-min reperfusion. We tested the hypothesis that signaling at the transcriptional level is followed by corresponding proteomic response and maintenance of structural integrity after 3-h reperfusion. Isolated hearts were Langendorff perfused and exposed to mild (I group; n = 6, 34 degrees C) or moderate (H group; n = 6, 30 degrees C) hypothermia during 120-min total ischemia with cardioplegic arrest and 180-min 37 degrees C reperfusion. Moderate hypothermia suppressed anaerobic metabolism during ischemia and significantly diminished left ventricular end-diastolic pressure at the end of ischemia from 52.7 +/- 3.3 (I group) to 1.8 +/- 0.9 (H group) mmHg. Unlike the I group, which showed poor cardiac function and high left ventricular pressure, the H group showed preservation of myocardial function, coronary flow, and oxygen consumption. Compared with normal control hearts without ischemia (n = 5), histological staining in the I group showed marked disarray and fragmentation of collagen network (score 4-5), while the H group showed preserved collagen integrity (score 0-1). The apoptosis-linked tumor suppressor protein p53 was expressed throughout the I group only (score 4-5). The H group produced elevated expression for hypoxia-inducible factor 1alpha and heme oxygenase 1, but minimally affected vascular endothelial growth factor expression. The H group also elevated expression for survival proteins peroxisomal proliferator-activated receptor-beta and Akt-1. These results show in a constant left ventricular volume model that moderate hypothermia (30 degrees C) decreases myocardial energy utilization during ischemia and subsequently promotes expression of proteins involved in cell survival, while inhibiting induction of p53 protein. These data also show that 34 degrees C proffers less protection and loss of myocardial integrity.

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