Cardioprotection of Immature Heart by Simultaneous Activation of PKA and Epac: A Role for the Mitochondrial Permeability Transition Pore.

Martin John Lewis,Igor Khaliulin,M Saadeh Suleiman,Katie Hall

doi:10.3390/ijms23031720

Martin John Lewis, Igor Khaliulin + Show 2 more

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https://doi.org/10.3390/ijms23031720

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Abstract

Metabolic and ionic changes during ischaemia predispose the heart to the damaging effects of reperfusion. Such changes and the resulting injury differ between immature and adult hearts. Therefore, cardioprotective strategies for adults must be tested in immature hearts. We have recently shown that the simultaneous activation of protein kinase A (PKA) and exchange protein activated by cAMP (Epac) confers marked cardioprotection in adult hearts. The aim of this study is to investigate the efficacy of this intervention in immature hearts and determine whether the mitochondrial permeability transition pore (MPTP) is involved. Isolated perfused Langendorff hearts from both adult and immature rats were exposed to global ischaemia and reperfusion injury (I/R) following control perfusion or perfusion after an equilibration period with activators of PKA and/or Epac. Functional outcome and reperfusion injury were measured and in parallel, mitochondria were isolated following 5 min of reperfusion to determine whether cardioprotective interventions involved changes in MPTP opening behaviour. Perfusion for 5 min preceding ischaemia of injury-matched adult and immature hearts with 5 µM 8-Br (8-Br-cAMP-AM), an activator of both PKA and Epac, led to significant reduction in post-reperfusion CK release and infarct size. Perfusion with this agent also led to a reduction in MPTP opening propensity in both adult and immature hearts. These data show that immature hearts are innately more resistant to I/R injury than adults, and that this is due to a reduced tendency of MPTP opening following reperfusion. Furthermore, simultaneous stimulation of PKA and Epac causes cardioprotection, which is additive to the innate resistance.

Highlights

Cardiac ischaemia/reperfusion (I/R) injury occurs during cardiac surgery [1], and is unavoidable due to the use of cardiac isolation through aortic cross-clamping and cessation of coronary blood flow
We investigated the cardioprotective efficacy of cAMP/protein kinase A (PKA) and cAMP/exchange protein activated by cAMP (Epac) signalling pathways in ex vivo perfused adult hearts and 14-day postnatal hearts exposed to global ischaemia/reperfusion
Having demonstrated the protective efficacy of simultaneous PKA and Epac activity in injury-matched P14 and adult rat hearts, we studied whether these agents were at least in part causing cardioprotection through inhibition of mitochondrial permeability transition pore (MPTP) opening induced by Ca2+ overload

Summary

Introduction

Cardiac ischaemia/reperfusion (I/R) injury occurs during cardiac surgery [1], and is unavoidable due to the use of cardiac isolation through aortic cross-clamping and cessation of coronary blood flow. It is a major contributor to morbidity and mortality [2]. The outcome from I/R injury is determined at least in part by the response of the mitochondria. Upon reperfusion of an ischaemic injury, a multimeric structure in the inner mitochondrial membrane known as the mitochondrial permeability transition pore, the MPTP, opens. The physiological function of this structure is not clear. It is known to have a central role in the pathogenesis of I/R injury

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