Suppression of Myocardial Hypoxia-Inducible Factor-1α Compromises Metabolic Adaptation and Impairs Cardiac Function in Patients With Cyanotic Congenital Heart Disease During Puberty
Suppression of Myocardial Hypoxia-Inducible Factor-1α Compromises Metabolic Adaptation and Impairs Cardiac Function in Patients With Cyanotic Congenital Heart Disease During Puberty
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DOI：
10.1161/circulationaha.120.051937
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发表时间：
2021-06-08
期刊：
影响因子：
37.8
通讯作者：
Zhang, Hao
中科院分区：
文献类型：
--
作者：
Liu, Yiwei;Luo, Qipeng;Zhang, Hao
背景：紫绀型先天性心脏病（CCHD）是一种复杂的病理生理状态，涉及全身慢性缺氧（CH）。一些患有CCHD的患者由于各种原因而未接受手术，并且在他们的一生中一直处于慢性缺氧状态，这增加了随着年龄的增长而发生心力衰竭的风险。缺氧激活细胞代谢适应，通过积累缺氧诱导因子1-α（HIF-1 α）来平衡能量需求。本研究旨在确定CH对CCHD患者心脏代谢和功能的影响及其与年龄的关系。HIF-1 α在这一过程中的作用进行了研究，并探讨了潜在的治疗靶点。方法：CCHD患者（n=25）进行了评估心脏代谢和功能与正电子发射断层扫描/计算机断层扫描和磁共振成像。心脏组织样本进行代谢组学和蛋白质分析。生成CH啮齿动物模型，以便能够连续观察心脏代谢和功能的变化。HIF-1 α在心脏代谢适应CH的作用进行了研究与转基因动物和同位素标记的代谢途径tracingstudies.Results：青春期前CCHD患者有葡萄糖占主导地位的心脏代谢和正常的心功能。相比之下，在进入青春期的患者中，心肌葡萄糖摄取和糖酵解中间产物的水平显著降低，但脂肪酸显著增加，沿着左心室射血分数降低。这些临床表型在CH啮齿动物模型中得到复制。在CCHD患者和暴露于CH的动物中，心肌HIF-1 α在青春期前上调，但在青春期显著下调。在心肌细胞特异性HIF-1 α基因敲除小鼠中，CH未能启动心肌底物从脂肪酸到葡萄糖的转换，从而抑制ATP的产生并损害心脏功能。青春期胰岛素抵抗增加抑制心肌HIF-1 α和心脏代谢适应不良的动物暴露于CH。吡格列酮显着降低心肌胰岛素抵抗，恢复葡萄糖代谢，改善心脏功能在青春期CH animals.Conclusions：在CCHD患者中，心脏代谢适应不良发生在青春期，沿着心功能受损。HIF-1 α被确定为暴露于CH的动物心脏代谢适应的关键调节因子，青春期胰岛素抵抗可抑制其表达。青春期服用吡格列酮可能有助于改善CCHD患者的心功能。
Background:Cyanotic congenital heart disease (CCHD) is a complex pathophysiological condition involving systemic chronic hypoxia (CH). Some patients with CCHD are unoperated for various reasons and remain chronically hypoxic throughout their lives, which heightens the risk of heart failure as they age. Hypoxia activates cellular metabolic adaptation to balance energy demands by accumulating hypoxia-inducible factor 1-alpha (HIF-1 alpha). This study aims to determine the effect of CH on cardiac metabolism and function in patients with CCHD and its association with age. The role of HIF-1 alpha in this process was investigated, and potential therapeutic targets were explored.Methods:Patients with CCHD (n=25) were evaluated for cardiac metabolism and function with positron emission tomography/computed tomography and magnetic resonance imaging. Heart tissue samples were subjected to metabolomic and protein analyses. CH rodent models were generated to enable continuous observation of changes in cardiac metabolism and function. The role of HIF-1 alpha in cardiac metabolic adaptation to CH was investigated with genetically modified animals and isotope-labeled metabolomic pathway tracing studies.Results:Prepubertal patients with CCHD had glucose-dominant cardiac metabolism and normal cardiac function. In comparison, among patients who had entered puberty, the levels of myocardial glucose uptake and glycolytic intermediates were significantly decreased, but fatty acids were significantly increased, along with decreased left ventricular ejection fraction. These clinical phenotypes were replicated in CH rodent models. In patients with CCHD and animals exposed to CH, myocardial HIF-1 alpha was upregulated before puberty but was significantly downregulated during puberty. In cardiomyocyte-specific Hif-1 alpha-knockout mice, CH failed to initiate the switch of myocardial substrates from fatty acids to glucose, thereby inhibiting ATP production and impairing cardiac function. Increased insulin resistance during puberty suppressed myocardial HIF-1 alpha and was responsible for cardiac metabolic maladaptation in animals exposed to CH. Pioglitazone significantly reduced myocardial insulin resistance, restored glucose metabolism, and improved cardiac function in pubertal CH animals.Conclusions:In patients with CCHD, maladaptation of cardiac metabolism occurred during puberty, along with impaired cardiac function. HIF-1 alpha was identified as the key regulator of cardiac metabolic adaptation in animals exposed to CH, and pubertal insulin resistance could suppress its expression. Pioglitazone administration during puberty might help improve cardiac function in patients with CCHD.