Moderate hypothermia (30°C) maintains myocardial integrity and modifies response of cell survival proteins after reperfusion

Abstract

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°C) or moderate (H group; n = 6, 30°C) hypothermia during 120-min total ischemia with cardioplegic arrest and 180-min 37°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 1α 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-β and Akt-1. These results show in a constant left ventricular volume model that moderate hypothermia (30°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°C proffers less protection and loss of myocardial integrity.