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Adverse Effects on ?-Adrenergic Receptor Coupling: Ischemic Postconditioning Failed to Preserve Long-Term Cardiac Function.

ABSTRACT: BACKGROUND:Ischemic preconditioning (IPC) and ischemic postconditioning (IPoC) are currently among the most efficient strategies protecting the heart against ischemia/reperfusion injury. However, the effect of IPC and IPoC on functional recovery following ischemia/reperfusion is less clear, particularly with regard to the specific receptor-mediated signaling of the postischemic heart. The current article examines the effect of IPC or IPoC on the regulation and coupling of ?-adrenergic receptors and their effects on postischemic left ventricular function. METHODS AND RESULTS:The ?-adrenergic signal transduction was analyzed in 3-month-old Wistar rats for each of the intervention strategies (Sham, ischemia/reperfusion, IPC, IPoC) immediately and 7 days after myocardial infarction. Directly after the infarction a cardioprotective potential was demonstrated for both IPC and IPoC: the infarct size was reduced, apoptosis and production of reactive oxygen species were lowered, and the myocardial tissue was preserved. Seven days after myocardial ischemia, only IPC hearts showed significant functional improvement. Along with a deterioration in fractional shortening, IPoC hearts no longer responded adequately to ?-adrenergic stimulation. The stabilization of ?-adrenergic receptor kinase-2 via increased phosphorylation of Mdm2 (an E3-ubiquitin ligase) was responsible for desensitization of ?-adrenergic receptors and identified as a characteristic specific to IPoC hearts. CONCLUSIONS:Immediately after myocardial infarction, rapid and transient activation of ?-adrenergic receptor kinase-2 may be an appropriate means to protect the injured heart from excessive stress. In the long term, however, induction and stabilization of ?-adrenergic receptor kinase-2, with the resultant loss of positive inotropic function, leads to the functional picture of heart failure.

SUBMITTER: Schreckenberg R

PROVIDER: S-EPMC5779008 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Adverse Effects on β-Adrenergic Receptor Coupling: Ischemic Postconditioning Failed to Preserve Long-Term Cardiac Function.

Schreckenberg Rolf R Bencsik Péter P Weber Martin M Abdallah Yaser Y Csonka Csaba C Gömöri Kamilla K Kiss Krisztina K Pálóczi János J Pipis Judit J Sárközy Márta M Ferdinandy Péter P Schulz Rainer R Schlüter Klaus-Dieter KD

Journal of the American Heart Association 20171222 12

<h4>Background</h4>Ischemic preconditioning (IPC) and ischemic postconditioning (IPoC) are currently among the most efficient strategies protecting the heart against ischemia/reperfusion injury. However, the effect of IPC and IPoC on functional recovery following ischemia/reperfusion is less clear, particularly with regard to the specific receptor-mediated signaling of the postischemic heart. The current article examines the effect of IPC or IPoC on the regulation and coupling of β-adrenergic re ...[more]

PMID: 29273639

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Project description:BackgroundOut-of-hospital cardiac arrest (CA) is a prevalent medical crisis resulting in severe injury to the heart and brain and an overall survival of less than 10%. Mitochondrial dysfunction is predicted to be a key determinant of poor outcomes following prolonged CA. However, the onset and severity of mitochondrial dysfunction during CA and cardiopulmonary resuscitation (CPR) is not fully understood. Ischemic postconditioning (IPC), controlled pauses during the initiation of CPR, has been shown to improve cardiac function and neurologically favorable outcomes after 15min of CA. We tested the hypothesis that mitochondrial dysfunction develops during prolonged CA and can be rescued with IPC during CPR (IPC-CPR).MethodsA total of 63 swine were randomized to no ischemia (Naïve), 19min of ventricular fibrillation (VF) CA without CPR (Untreated VF), or 15min of CA with 4min of reperfusion with either standard CPR (S-CPR) or IPC-CPR. Mitochondria were isolated from the heart and brain to quantify respiration, rate of ATP synthesis, and calcium retention capacity (CRC). Reactive oxygen species (ROS) production was quantified from fresh frozen heart and brain tissue.ResultsCompared to Naïve, Untreated VF induced cardiac and brain ROS overproduction concurrent with decreased mitochondrial respiratory coupling and CRC, as well as decreased cardiac ATP synthesis. Compared to Untreated VF, S-CPR attenuated brain ROS overproduction but had no other effect on mitochondrial function in the heart or brain. Compared to Untreated VF, IPC-CPR improved cardiac mitochondrial respiratory coupling and rate of ATP synthesis, and decreased ROS overproduction in the heart and brain.ConclusionsFifteen minutes of VF CA results in diminished mitochondrial respiration, ATP synthesis, CRC, and increased ROS production in the heart and brain. IPC-CPR attenuates cardiac mitochondrial dysfunction caused by prolonged VF CA after only 4min of reperfusion, suggesting that IPC-CPR is an effective intervention to reduce cardiac injury. However, reperfusion with both CPR methods had limited effect on mitochondrial function in the brain, emphasizing an important physiological divergence in post-arrest recovery between those two vital organs.

Dataset Information

Adverse Effects on ?-Adrenergic Receptor Coupling: Ischemic Postconditioning Failed to Preserve Long-Term Cardiac Function.

Publications

Adverse Effects on β-Adrenergic Receptor Coupling: Ischemic Postconditioning Failed to Preserve Long-Term Cardiac Function.

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