Abstract 5331: Gene Transfer Of The Peripheral Type Benzodiazepine Receptor Alters The Spatio-temporal Dynamics Of The Mitochondrial Membrane Potential (ΔΨM) Across The Intact Heart
The peripheral type benzodiazepine receptor (mBZR) is a key mediator of mitochondrial dysfunction during oxidative stress. In isolated cardiomyocytes agonists of the mBZR cause ΔΨm depolarization, KATP channel activation, and subsequent loss of cellular excitability. However, the spatiotemporal dynamics of ΔΨm in the intact heart and their relationship to arrhythmias are unknown. Here, we investigate the mechanistic link between mBZR and ΔΨm directly using adenoviral mediated gene transfer of the mBZR encoding gene (PKBS) in rat myocardium.
Methods: Optical imaging was performed at a subcellular resolution in ex vivo perfused hearts from AdPKBS (n=5), AdGFP (n=2), and normal (n=4) rats. Normalized ΔΨm was measured using a novel quantitative technique of TMRM imaging during global ischemia (7.5 min) followed by reperfusion. Mean and SD of baseline corrected & normalized ΔΨm across 6400 sites were compared between groups.
Results: In sharp contrast to normal and GFP groups, 4 of 5 PKBS hearts exhibited a paradoxical increase in ΔΨm during ischemia (Fig A⇓) as ΔΨm was significantly (p<0.05) greater in PKBS (+0.18±0.07) compared to GFP (−0.62±0.21) and normal hearts (−0.17±0.16) following 7.5min of ischemia. A transient overshoot in ΔΨm observed in all groups during early (<30sec) reperfusion was greatest in PKBS hearts (Fig A⇓). Finally, ΔΨm heterogeneity indexed by SD was markedly greater in PKBS compared to GFP and normal hearts during ischemia (p<0.01) and reperfusion (p<0.01) (Fig B⇓).
Conclusion: PKBS alters spatiotemporal dynamics of ΔΨm and increases ΔΨm heterogeneity across the intact heart. Modulating PKBS expression may be a novel therapeutic strategy for arrhythmias.