Institute of Physiology, University of Duisburg-Essen, Essen, Germany.
Basic Res Cardiol. 2019 Mar 11;114(3):16. doi: 10.1007/s00395-019-0725-2.
A major challenge in developing new treatments for myocardial infarction (MI) is an improved understanding of the pathophysiology of hypoxic tissue damage and the activation of endogenous adaptive programs to hypoxia. Due to the relevance of oxygen in metabolism, molecular adaptation to hypoxia driven by the hypoxia-inducible factors (HIFs) and the HIF-regulating prolyl hydroxylase domain enzymes (PHDs) is pivotal for the survival of cells and tissue under hypoxia. The heart under ischemic stress will extensively rely on these mechanisms of endogenous cardiac protection until hypoxia becomes too severe. In the past, work from several laboratories has provided evidence that inhibition of HIF-regulating PHDs might improve the outcome in ischemic heart disease (IHD) potentially because the adaptive mechanisms are boosted early and vigorously. Here, we review the role of the HIF hydroxylase pathway in IHD and highlight the potential of PHD inhibitors as a new treatment for MI with special regard to acute ischemia, reperfusion, and regeneration of the heart.
在开发心肌梗死 (MI) 新疗法方面，面临的一个主要挑战是更深入地了解缺氧组织损伤的病理生理学和对缺氧的内源性适应程序的激活。由于氧在新陈代谢中的重要性，缺氧诱导因子 (HIF) 驱动的分子对缺氧的适应和 HIF 调节脯氨酰羟化酶结构域酶 (PHD) 对于细胞和组织在缺氧下的存活至关重要。在缺血应激下，心脏将广泛依赖这些内源性心脏保护机制，直到缺氧变得过于严重。过去，几个实验室的工作提供了证据，表明抑制 HIF 调节的 PHD 可能会改善缺血性心脏病 (IHD) 的预后，这可能是因为早期和强有力地增强了适应性机制。在这里，我们综述了 HIF 羟化酶通路在 IHD 中的作用，并强调了 PHD 抑制剂作为 MI 新疗法的潜力，特别是在急性缺血、再灌注和心脏再生方面。
