Hypothermia preserves myocardial function and mitochondrial protein gene expression during hypoxia

Abstract

Hypothermia before and/or during no-flow ischemia promotes cardiac functional recovery and maintains mRNA expression for stress proteins and mitochondrial membrane proteins (MMP) during reperfusion. Adaptation and protection may occur through cold-induced change in anaerobic metabolism. Accordingly, the principal objective of this study was to test the hypothesis that hypothermia preserves myocardial function during hypoxia and reoxygenation. Hypoxic conditions in these experiments were created by reducing O 2 concentration in perfusate, thereby maintaining or elevating coronary flow (CF). Isolated Langendorff-perfused rabbit hearts were subjected to perfusate (PO 2 ϭ 38 mmHg) with glucose (11.5 mM) and perfusion pressure (90 mmHg). The control (C) group was at 37°C for 30 min before and 45 min during hypoxia, whereas the hypothermia (H) group was at 29.5°C for 30 min before and 45 min during hypoxia. Reoxygenation occurred at 37°C for 45 min for both groups. CF increased during hypoxia. The H group markedly improved functional recovery during reoxygenation, including left ventricular developed pressure (DP), the product of DP and heart rate, dP/dt max, and O2 consumption (MVO2) (P Ͻ 0.05 vs. control). MVO 2 decreased during hypothermia. Lactate and CO 2 gradients across the coronary bed were the same in C and H groups during hypoxia, implying similar anaerobic metabolic rates. Hypothermia preserved MMP ␤F 1-ATPase mRNA levels but did not alter adenine nucleotide translocator-1 or heat shock protein-70 mRNA levels. In conclusion, hypothermia preserves cardiac function after hypoxia in the hypoxic high-CF model. Thus hypothermic protection does not occur exclusively through cold-induced alterations in anaerobic metabolism. lactate; mitochondrial membrane protein; myocardial ischemia; reperfusion EVALUATION OF HYPOTHERMIC myocardial protection has occurred predominantly in experimental models employing reductions in coronary flow to reduce oxygen supply. Exposure to mild or moderate hypothermic insult promotes cross-tolerance to variable forms of subsequent injury, particularly those produced by ischemia and/or reperfusion (19,21). A reduction in ATP utilization rate initiated by hypothermia persists during rewarming and plays a central role in preserving myocardial function after ischemia and reperfusion (20). Hypothermic ATP preservation may promote specific molecular responses observed during reperfusion in the isolated rabbit heart model, including stabilization of steady-state mRNA levels for nuclear-encoded mitochondrial membrane proteins, enhanced induction of the stress protein heat shock protein-70 (HSP70) (19,21,22) and promotion of signaling for antiapoptotic pathways (18).Hypothermia under no-flow conditions also reduces anaerobic ATP synthesis, thereby minimizing accumulation of glycolytic end products and raising myocardial pH (21). The anaerobic metabolites are known to exacerbate myocardial injury during reperfusion and to putatively regulate signaling for heat shock responses (15). Thus the hypoth...

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