Intra‐ischemic hypothermia cardioprotection involves modulation of PTEN/Akt/ERK signaling and fatty acid oxidation

• Published in: Physiological reports 2023-02, Vol.11 (4), p.e15611-n/a
• Main Authors: Justice, Cody N., Zhu, Xiangdong, Li, Jing, O'Donnell, J. Michael, Vanden Hoek, Terry L.
• Format: Article
• Language: English
• Subjects: AKT protein; Animals; Cooling; Extracellular signal-regulated kinase; fatty acid oxidation; Fatty Acids; Glucose; Heart; Heart rate; Hemodynamics; Hypothermia; Ischemia; ischemia/reperfusion; Kinases; Laboratory animals; MAP Kinase Signaling System; Metabolism; Metabolites; Myocardial Reperfusion Injury; Original; Oxidation; Phosphorylation; Physiology; Proto-Oncogene Proteins c-akt - metabolism; PTEN; PTEN Phosphohydrolase - metabolism; PTEN protein; Pulmonary arteries; Rats; Reperfusion; Taurine; therapeutic hypothermia; Ventricle
• ISSN: 2051-817X; 2051-817X
• DOI: 10.14814/phy2.15611

Therapeutic hypothermia (TH) provides cardioprotection from ischemia/reperfusion (I/R) injury. However, it remains unknown how TH regulates metabolic recovery. We tested the hypothesis that TH modulates PTEN, Akt, and ERK1/2, and improves metabolic recovery through mitigation of fatty acid oxidation and taurine release. Left ventricular function was monitored continuously in isolated rat hearts subjected to 20 min of global, no‐flow ischemia. Moderate cooling (30°C) was applied at the start of ischemia and hearts were rewarmed after 10 min of reperfusion. The effect of TH on protein phosphorylation and expression at 0 and 30 min of reperfusion was investigated by western blot analysis. Post‐ischemic cardiac metabolism was investigated by 13C‐NMR. TH enhanced recovery of cardiac function, reduced taurine release, and enhanced PTEN phosphorylation and expression. Phosphorylation of Akt and ERK1/2 was increased at the end of ischemia but decreased at the end of reperfusion. On NMR analysis, TH‐treated hearts displayed decreased fatty acid oxidation. Direct cardioprotection by moderate intra‐ischemic TH is associated with decreased fatty acid oxidation, reduced taurine release, enhanced PTEN phosphorylation and expression, and enhanced activation of both Akt and ERK1/2 prior to reperfusion. The present study reveals a new metabolic mechanism that moderate intra‐ischemic hypothermia improves cardiac function against ischemia/reperfusion injury involving the inhibition of fatty acid oxidation in an isolated heart model. Hypothermia also reduces taurine release and modulates PTEN/Akt/ERK signaling during ischemia and reperfusion.