Hypoxic regulation of hand1 controls the fetal-neonatal switch in cardiac metabolism.
Hypoxic regulation of hand1 controls the fetal-neonatal switch in cardiac metabolism.
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DOI：
10.1371/journal.pbio.1001666
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发表时间：
2013-09
期刊：
影响因子：
9.8
通讯作者：
Mohun TJ
中科院分区：
文献类型：
--
作者：
Breckenridge RA;Piotrowska I;Ng KE;Ragan TJ;West JA;Kotecha S;Towers N;Bennett M;Kienesberger PC;Smolenski RT;Siddall HK;Offer JL;Mocanu MM;Yelon DM;Dyck JR;Griffin JL;Abramov AY;Gould AP;Mohun TJ
这项研究揭示了一种新的途径，该途径响应缺氧并调节小鼠心脏中心肌细胞的能量代谢，从而确定耗氧量。心肌细胞在成年时易受缺氧的影响，但在子宫内适应缺氧。目前对内源性心脏氧传感通路的理解是有限的。心肌耗氧量是由能量代谢的调节决定的，出生后不久，能量代谢从糖酵解转变为脂质氧化，并且在衰竭的成人心脏中逆转，伴随着几个“胎儿”基因的重新表达，这些基因在疾病表型中的作用仍然未知。在这里，我们表明，缺氧控制的转录因子Hand1的表达决定通过抑制胎儿和成人心肌细胞中的脂质代谢，导致线粒体能量产生的下调耗氧量。Hand1受HIF 1 α的直接转录控制。延长心脏Hand1表达的转基因小鼠在出生后立即死亡，未能激活新生儿脂质代谢基因表达程序。胚胎心肌细胞中Hand1的缺失导致这些基因的过早表达。使用代谢通量分析，我们表明，手1表达控制心肌细胞耗氧量的脂质代谢基因的直接转录抑制。这又导致葡萄糖产生乳酸的增加、脂质氧化的减少、线粒体内膜电位的降低和线粒体ATP的产生。我们发现，这一途径是活跃在成年心肌细胞。Hand 1的上调在心肌缺血小鼠模型中具有保护作用。我们认为Hand1是连接心脏氧水平与氧消耗的新型调节途径的一部分。了解胎儿心脏的缺氧适应可能有助于制定保护易受缺血影响的心肌细胞的策略，例如在心脏缺血或手术期间。心肌细胞中氧利用的调节具有极大的医学意义，因为成人心脏组织在心肌梗死和心脏手术期间极易受到缺氧的影响。虽然在这些情况下已经取得了一些进展，以保护心肌细胞免受缺氧，但由于缺乏对内源性氧敏感途径的了解，它受到了限制。与成人心肌组织相比，胚胎心肌细胞对缺氧具有高度耐受性，尽管其机制迄今尚不清楚。使用小鼠，我们发现转录因子Hand1在胎儿心脏中高水平表达，受HIF 1 α信号传导的直接控制，HIF 1 α信号传导是一种众所周知的对缺氧反应的途径。我们发现，Hand1表达在出生时降低，因为新生儿暴露于更高水平的氧气。通过实验增加Hand1在新生儿心脏中的表达，我们看到心肌细胞的耗氧量较低，这是由于Hand1抑制参与心肌细胞脂质代谢的关键调控基因所致。这具有通过三羧酸循环减少线粒体ATP生成的作用。此外，我们发现，增加Hand1在成人转基因心脏表达是保护心肌梗死，这表明缺氧Hand1通路也可能是在成人心脏的重要性。
This study reveals a novel pathway that responds to hypoxia and modulates energy metabolism by cardiomyocytes in the mouse heart, thereby determining oxygen consumption. Cardiomyocytes are vulnerable to hypoxia in the adult, but adapted to hypoxia in utero. Current understanding of endogenous cardiac oxygen sensing pathways is limited. Myocardial oxygen consumption is determined by regulation of energy metabolism, which shifts from glycolysis to lipid oxidation soon after birth, and is reversed in failing adult hearts, accompanying re-expression of several “fetal” genes whose role in disease phenotypes remains unknown. Here we show that hypoxia-controlled expression of the transcription factor Hand1 determines oxygen consumption by inhibition of lipid metabolism in the fetal and adult cardiomyocyte, leading to downregulation of mitochondrial energy generation. Hand1 is under direct transcriptional control by HIF1α. Transgenic mice prolonging cardiac Hand1 expression die immediately following birth, failing to activate the neonatal lipid metabolising gene expression programme. Deletion of Hand1 in embryonic cardiomyocytes results in premature expression of these genes. Using metabolic flux analysis, we show that Hand1 expression controls cardiomyocyte oxygen consumption by direct transcriptional repression of lipid metabolising genes. This leads, in turn, to increased production of lactate from glucose, decreased lipid oxidation, reduced inner mitochondrial membrane potential, and mitochondrial ATP generation. We found that this pathway is active in adult cardiomyocytes. Up-regulation of Hand1 is protective in a mouse model of myocardial ischaemia. We propose that Hand1 is part of a novel regulatory pathway linking cardiac oxygen levels with oxygen consumption. Understanding hypoxia adaptation in the fetal heart may allow development of strategies to protect cardiomyocytes vulnerable to ischaemia, for example during cardiac ischaemia or surgery. Regulation of oxygen usage in cardiomyocytes is of great medical interest, because adult cardiac tissue is extremely vulnerable to hypoxia during myocardial infarction and cardiac surgery. While some progress has been made toward protecting cardiomyocytes from hypoxia in these circumstances, it has been limited by a lack of understanding of endogenous oxygen-sensing pathways. In contrast to adult cardiac tissue, embryonic cardiomyocytes are highly resistant to hypoxia, although the mechanisms underlying this have hitherto been unclear. Using mice we show that the transcription factor Hand1 is expressed at high levels in the fetal heart, under direct control of HIF1α signaling, a pathway well known to respond to hypoxia. We show that Hand1 expression decreases at birth as the neonate is exposed to higher levels of oxygen. By experimentally increasing Hand1 expression in the neonatal heart, we see lower oxygen consumption in cardiomyocytes and this is caused by Hand1 repressing key regulatory genes involved in cardiomyocyte lipid metabolism. This has the effect of decreasing mitochondrial ATP generation via the tricarboxylic acid cycle. Furthermore, we show that increasing Hand1 expression in adult transgenic hearts is protective against myocardial infarction, suggesting that a hypoxia–Hand1 pathway may also be of importance in the adult heart.
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