恒河猴心脏缺血损伤后 HIF-1 信号的动态调控。
Dynamic regulation of HIF-1 signaling in the rhesus monkey heart after ischemic injury.
机构信息
Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
出版信息
BMC Cardiovasc Disord. 2022 Sep 11;22(1):407. doi: 10.1186/s12872-022-02841-0.
BACKGROUND
Hypoxia inducible factor-1 (HIF-1) plays a key role in modulating post-infarct healing after myocardial ischemic injury through transcriptional regulation of hundreds of genes involved in diverse cardiac remodeling processes. However, the dynamic changes in HIF-1 target gene expression in the ischemic heart after myocardial infarction (MI) have not been well characterized.
METHODS
We employed a rhesus monkey model of MI induced by left anterior descending artery ligation and examined the expression pattern of HIF-1 target genes in the ischemic heart at 1, 7, and 28 days after injury by bulk RNA-sequencing analysis.
RESULTS
Myocardial transcriptomic analysis demonstrated a temporal-specific regulation of genes associated with the inflammatory response, cell proliferation, fibrosis and mitochondrial metabolism during the pathological progression of MI. HIF-1 target genes involved in processes related to glycolysis, angiogenesis, and extracellular matrix (ECM) remodeling also exhibited distinct expression patterns during MI progression. Copper concentrations were gradually decreased in the heart after ischemic injury, which was positively correlated with the expression of HIF-1-mediated angiogenic and glycolytic genes but negatively correlated with the expression of HIF-1-mediated ECM remodeling genes. Moreover, genes related to intracellular copper trafficking and storage were suppressed along with the loss of myocardial copper in the ischemic heart.
CONCLUSIONS
This study demonstrated a dynamic, functional-specific regulation of HIF-1 target gene expression during the progression of MI. The fine-tuning of HIF-1 signaling in the ischemic heart may be relate to the alteration in myocardial copper homeostasis. These findings provide transcriptomic insights into the distinct roles of HIF-1 signaling in the heart after ischemic injury, which will help determine the beneficial cutoff point for HIF-1 targeted therapy in ischemic heart diseases.
背景
缺氧诱导因子-1（HIF-1）通过转录调控参与多种心脏重构过程的数百个基因，在心肌缺血损伤后调节梗死区愈合中发挥关键作用。然而，心肌梗死后缺血心脏中 HIF-1 靶基因表达的动态变化尚未得到很好的描述。
方法
我们采用左前降支结扎诱导的恒河猴心肌梗死模型，通过 bulk RNA-seq 分析检测损伤后 1、7 和 28 天缺血心脏中 HIF-1 靶基因的表达模式。
结果
心肌转录组分析表明，在 MI 的病理进展过程中，与炎症反应、细胞增殖、纤维化和线粒体代谢相关的基因呈现出时间特异性调节。与糖酵解、血管生成和细胞外基质（ECM）重塑相关的 HIF-1 靶基因在 MI 进展过程中也表现出不同的表达模式。缺血损伤后心脏内铜浓度逐渐降低，与 HIF-1 介导的血管生成和糖酵解基因的表达呈正相关，但与 HIF-1 介导的 ECM 重塑基因的表达呈负相关。此外，与细胞内铜转运和储存相关的基因随着缺血心脏中心肌铜的丢失而被抑制。
结论
本研究表明，在 MI 进展过程中，HIF-1 靶基因表达呈现动态、功能特异性调节。缺血心脏中 HIF-1 信号的精细调节可能与心肌铜稳态的改变有关。这些发现为 HIF-1 信号在缺血性心脏损伤后在心脏中的不同作用提供了转录组学见解，有助于确定缺血性心脏病中 HIF-1 靶向治疗的有益截止点。
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