Pre- and post-conditional inhibition of prolyl-4-hydroxylase domain enzymes protects the heart from an ischemic insult
Pre- and post-conditional inhibition of prolyl-4-hydroxylase domain enzymes protects the heart from an ischemic insult
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DOI：
10.1007/s00424-014-1667-z
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发表时间：
2015-01
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通讯作者：
Melanie Vogler;A. Zieseniss;Amke R. Hesse;Elif Levent;M. Tiburcy;E. Heinze;N. Burzlaff;G. Schley
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文献类型：
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作者：
Melanie Vogler;A. Zieseniss;Amke R. Hesse;Elif Levent;M. Tiburcy;E. Heinze;N. Burzlaff;G. Schley
几种转基因小鼠模型表明，Pro-4-羟基酶结构域(PHD)酶通过影响缺氧诱导因子(HIF)-1和HIF-2的稳定性和活化，是保护组织免受包括心肌梗死在内的缺血性损伤的关键介质。因此，目前开发小分子PHD抑制剂的努力为缺血期间的心肌组织保护开辟了一种新的治疗选择。因此，我们旨在研究一种小分子PHD抑制剂在心脏中稳定低氧诱导因子α的适用性和有效性。我们测试了在心肌梗死急性期应用抑制剂前或条件后的保护作用。PHD特异性抑制剂2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido)乙酸酯(ICA)在体内外均可引起心肌细胞HIF-1α和HIF-2α积聚。已知的HIF靶基因血红素氧合酶-1和PHD3的诱导进一步证实了心脏组织对ICA的快速和强大的反应性。心肌梗死小鼠在条件治疗前和条件治疗后，心肌梗死面积显著缩小。条件前或条件后ICA治疗对组织缺血的保护表明，心肌梗死后应用PhD抑制剂(PHI)有一个治疗时间窗口，这可能被用于急性医疗干预。
Several genetically modified mouse models implicated that prolyl-4-hydroxylase domain (PHD) enzymes are critical mediators for protecting tissues from an ischemic insult including myocardial infarction by affecting the stability and activation of hypoxia-inducible factor (HIF)-1 and HIF-2. Thus, the current efforts to develop small-molecule PHD inhibitors open a new therapeutic option for myocardial tissue protection during ischemia. Therefore, we aimed to investigate the applicability and efficacy of pharmacological HIFα stabilization by a small-molecule PHD inhibitor in the heart. We tested for protective effects in the acute phase of myocardial infarction after pre- or post-conditional application of the inhibitor. Application of the specific PHD inhibitor 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate (ICA) resulted in HIF-1α and HIF-2α accumulation in heart muscle cells in vitro and in vivo. The rapid and robust responsiveness of cardiac tissue towards ICA was further confirmed by induction of the known HIF target genes heme oxygenase-1 and PHD3. Pre- and post-conditional treatment of mice undergoing myocardial infarction resulted in a significantly smaller infarct size. Tissue protection from ischemia after pre- or post-conditional ICA treatment demonstrates that there is a therapeutic time window for the application of the PHD inhibitor (PHI) post-myocardial infarction, which might be exploited for acute medical interventions.