Blockade of Electron Transport at the Onset of Reperfusion Decreases Cardiac Injury in Aged Hearts by Protecting the Inner Mitochondrial Membrane

Abstract

Myocardial injury is increased in the aged heart following ischemia-reperfusion (ISC-REP) compared to adult hearts. Intervention at REP with ischemic postconditioning decreases injury in the adult heart by attenuating mitochondrial driven cell injury. Unfortunately, postconditioning is ineffective in aged hearts. Blockade of electron transport at the onset of REP with the reversible inhibitor amobarbital (AMO) decreases injury in adult hearts. We tested if AMO treatment at REP protects the aged heart via preservation of mitochondrial integrity. Buffer-perfused elderly Fischer 344 24 mo. rat hearts underwent 25 min global ISC and 30 min REP. AMO (2.5 mM) or vehicle was given for 3 min at the onset of REP. Subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria were isolated after REP. Oxidative phosphorylation (OXPHOS) and mitochondrial inner membrane potential were measured. AMO treatment at REP decreased cardiac injury. Compared to untreated ISC-REP, AMO improved inner membrane potential in SSM and IFM during REP, indicating preserved inner membrane integrity. Thus, direct pharmacologic modulation of electron transport at REP protects mitochondria and decreases cardiac injury in the aged heart, even when signaling-induced pathways of postconditioning that are upstream of mitochondria are ineffective.

Blockade of electron transport before ischemia protects mitochondria and decreases myocardial injury during reperfusion in aged rat hearts

“…The brief, transient blockade of electron transport by amobarbital at the onset of reperfusion decreases myocardial injury in adult rat heart 15; 57 and rabbit heart. 57; 58 Initial results in the aged heart 59 suggest that the modulation of electron transport for a brief period at the onset of reperfusion reduces injury consistent with the important principal advanced in the present study.…”

Proteomic Profiling Reveals Adaptive Responses to Surgical Myocardial Ischemia–Reperfusion in Hibernating Arctic Ground Squirrels Compared to Rats

“…Consistent with these findings, reversible pharmacological blockade of electron transport at the onset of reperfusion was recently reported to decrease cardiac injury in aged hearts by improving the inner mitochondrial membrane potential. 32 …”

Physiological and structural differences in spatially distinct subpopulations of cardiac mitochondria: influence of cardiac pathologies

“…These authors suggest that during early minutes of reperfusion, postconditioning reduces oxidative stress and inhibits mPTP opening independent of alteration in oxidative phosphorylation and mitochondrial membrane potential (94). Fischer 344 rat hearts undergoing 25 min of global ischemia and 30 min of reperfusion when treated with amobarbital for 3 min at the onset of reperfusion display decreased cardiac injury as well as improved IMM potential in both subpopulations, indicating preserved IMM integrity (15). Using a Langendorff perfused rat heart model of 25 min of global ischemia followed by 30 min of reperfusion, Chen et al (14) reported improved Ca 2ϩ tolerance and IMM potential in the SSM subpopulation.…”

“…Inherently, aging has been shown to decrease IFM oxidative metabolism; however, Lesnefsky et al (73) observed restoration of ETC complexes III and IV activities and oxidative phosphorylation in the IFM following 25 min of ischemia and 30 min of reperfusion in the aged rat heart pretreated with acetylcarnitine. Using a similar I/R protocol, Chen et al (15) observed preservation of IMM potential and integrity in both SSM and IFM when amobarbital treatment was presented at reperfusion. Taken together, these studies indicate that pharmacological modulation of electron transport may present an avenue for decreasing mitochondrial injury brought about by I/R in the aged heart.…”