Cardioprotection of Immature Heart by Simultaneous Activation of PKA and Epac: A Role for the Mitochondrial Permeability Transition Pore.
Cardioprotection of Immature Heart by Simultaneous Activation of PKA and Epac: A Role for the Mitochondrial Permeability Transition Pore.
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DOI：
10.3390/ijms23031720
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发表时间：
2022-02-02
影响因子：
5.6
通讯作者：
Suleiman MS
中科院分区：
文献类型：
--
作者：
Lewis MJ;Khaliulin I;Hall K;Suleiman MS
缺血期间代谢和离子的变化使心脏易受再灌注损伤。这种变化和由此产生的损伤在未成熟和成年心脏之间是不同的。因此，成人的心脏保护策略必须在未成熟的心脏中进行测试。我们最近发现，蛋白激酶A（PKA）和交换蛋白激活cAMP（Epac）的同时激活赋予显着的心脏保护在成人心脏。本研究的目的是调查这种干预在未成熟心脏中的疗效，并确定是否涉及线粒体通透性转换孔（MPTP）。分离灌注Langendorff心脏从成年和未成年大鼠暴露于全球缺血和再灌注损伤（I/R）控制灌注或灌注后的平衡期与PKA和/或Epac的激活剂。功能结果和再灌注损伤进行了测量，并在平行，线粒体分离后5分钟的再灌注，以确定是否心脏保护干预措施涉及MPTP开放行为的变化。在损伤匹配的成人和未成熟心脏缺血前用5 μM 8-Br（8-Br-cAMP-AM）（PKA和Epac的激活剂）灌注5分钟，导致再灌注后CK释放和梗死面积显著减少。灌注这种药物还导致成人和未成熟心脏的MPTP开放倾向降低。这些数据表明，未成熟的心脏天生比成年人更能抵抗I/R损伤，这是由于再灌注后MPTP开放的趋势降低。此外，PKA和Epac的同时刺激引起心脏保护，这是先天抗性的附加物。
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.
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DOI：
10.1073/pnas.0812536106
发表时间：
2009-08-18
影响因子：
11.1
作者：
Cazorla, Olivier;Lucas, Alexandre;Lezoualc'h, Frank
通讯作者：
Lezoualc'h, Frank
影响因子：
10.8
作者：
Dekker, LRC;Coronel, R;Opthof, T
通讯作者：
Opthof, T
DOI：
10.1196/annals.1341.022
发表时间：
2005-01-01
期刊：
COMMUNICATIVE CARDIAC CELL
影响因子：
--
作者：
Honda, HM;Korge, P;Weiss, JN
通讯作者：
Weiss, JN
影响因子：
37.8
作者：
Lochner, A;Genade, S;Moolman, JA
通讯作者：
Moolman, JA
影响因子：
7.3
作者：
Khaliulin I;Bond M;James AF;Dyar Z;Amini R;Johnson JL;Suleiman MS
通讯作者：
Suleiman MS