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β-肾上腺素能受体偶联的不良反应:缺血后处理未能保留长期心脏功能。

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

机构信息

Physiologisches Institut, Justus-Liebig-Universität Gießen, Gießen, Germany

Pharmahungary Group, Szeged, Hungary.

出版信息

J Am Heart Assoc. 2017 Dec 22;6(12):e006809. doi: 10.1161/JAHA.117.006809.

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 β-adrenergic receptors and their effects on postischemic left ventricular function.

METHODS AND RESULTS

The β-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 β-adrenergic stimulation. The stabilization of β-adrenergic receptor kinase-2 via increased phosphorylation of Mdm2 (an E3-ubiquitin ligase) was responsible for desensitization of β-adrenergic receptors and identified as a characteristic specific to IPoC hearts.

CONCLUSIONS

Immediately after myocardial infarction, rapid and transient activation of β-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 β-adrenergic receptor kinase-2, with the resultant loss of positive inotropic function, leads to the functional picture of heart failure.

摘要

背景

缺血预处理(IPC)和缺血后处理(IPoC)是目前保护心脏免受缺血/再灌注损伤最有效的策略之一。然而,IPC 和 IPoC 对缺血/再灌注后心功能恢复的影响尚不清楚,特别是涉及到缺血后心脏的特定受体介导的信号转导。本文研究了 IPC 或 IPoC 对β肾上腺素能受体的调节和偶联及其对缺血后左心室功能的影响。

方法和结果

在 3 个月大的 Wistar 大鼠中,分析了每个干预策略(假手术、缺血/再灌注、IPC、IPoC)的β肾上腺素能信号转导,分别在心肌梗死即刻和 7 天后进行。心肌梗死后,IPC 和 IPoC 均显示出潜在的心脏保护作用:梗死面积减小,细胞凋亡和活性氧生成减少,心肌组织得到保存。心肌缺血 7 天后,只有 IPC 心脏显示出明显的功能改善。随着分数缩短的恶化,IPoC 心脏对β肾上腺素能刺激不再有足够的反应。通过增加 Mdm2(一种 E3 泛素连接酶)的磷酸化来稳定β肾上腺素能受体激酶-2,导致β肾上腺素能受体脱敏,并被确定为 IPoC 心脏的特征。

结论

心肌梗死后立即,β肾上腺素能受体激酶-2的快速和短暂激活可能是保护受损心脏免受过度应激的适当手段。然而,在长期内,β肾上腺素能受体激酶-2的诱导和稳定,以及随之而来的正性肌力功能丧失,导致心力衰竭的功能表现。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f6f9/5779008/d64f6838378f/JAH3-6-e006809-g001.jpg

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