<br>HIF 诱导 DEPP1 介导缺血性心肌病的多种特征。,Circulation

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HIF 诱导 DEPP1 介导缺血性心肌病的多种特征。
Circulation ( IF 35.5 ) Pub Date : 2024-06-17 , DOI: 10.1161/circulationaha.123.066628
Gregory A Wyant _{1,

2} , Qinqin Jiang ₁ , Madhu Singh ₂ , Shariq Qayyum ₂ , Clara Levrero ₁ , Bradley A Maron ₃ , William G Kaelin _{1,

4,

5}

Affiliation

背景 HIF（缺氧诱导因子）调节心脏功能的许多方面。我们和其他人之前表明，小鼠模型心脏中的慢性 HIF 激活与人类缺血性心肌病的多种特征相似，包括线粒体丢失、脂质积累和收缩性心功能障碍。在某些情况下，HIF 还会导致过氧化物酶体损失。从机制上讲，HIF 如何促进心脏功能障碍是一个悬而未决的问题。方法我们使用缺乏心脏 pVHL（von Hippel-Lindau 蛋白）的小鼠来研究慢性 HIF 激活如何导致缺血性心肌病的多种特征，例如自噬诱导和脂质积累。我们对分离的心肌细胞进行了免疫印迹分析、RNA 测序、线粒体和过氧化物酶体自噬通量测量以及活细胞成像。我们在小鼠中使用 CRISPR-Cas9 基因编辑来验证慢性 HIF 激活情况下心脏功能障碍的新型介质。结果我们确定了一条以前未知的途径，心脏 HIF 激活通过该途径促进线粒体和过氧化物酶体的损失。我们发现 DEPP1（黄体酮 1 诱导的蜕膜蛋白）在缺氧条件下以 HIF 依赖性方式被诱导，并定位于线粒体内。 DEPP1对于离体心肌细胞中缺氧诱导的自噬和甘油三酯积累是必要且充分的。在离体慢性 HIF 激活的情况下，DEPP1 缺失可增加心肌细胞的存活率，而全身 Depp1 缺失可减少体内 VHL 缺失引起的慢性 HIF 激活的心脏的心功能障碍。结论我们的研究结果表明 DEPP1 是慢性缺血引起的心脏重塑的关键组成部分。

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Induction of DEPP1 by HIF Mediates Multiple Hallmarks of Ischemic Cardiomyopathy.

BACKGROUND HIF (hypoxia inducible factor) regulates many aspects of cardiac function. We and others previously showed that chronic HIF activation in the heart in mouse models phenocopies multiple features of ischemic cardiomyopathy in humans, including mitochondrial loss, lipid accumulation, and systolic cardiac dysfunction. In some settings, HIF also causes the loss of peroxisomes. How, mechanistically, HIF promotes cardiac dysfunction is an open question. METHODS We used mice lacking cardiac pVHL (von Hippel-Lindau protein) to investigate how chronic HIF activation causes multiple features of ischemic cardiomyopathy, such as autophagy induction and lipid accumulation. We performed immunoblot assays, RNA sequencing, mitochondrial and peroxisomal autophagy flux measurements, and live cell imaging on isolated cardiomyocytes. We used CRISPR-Cas9 gene editing in mice to validate a novel mediator of cardiac dysfunction in the setting of chronic HIF activation. RESULTS We identify a previously unknown pathway by which cardiac HIF activation promotes the loss of mitochondria and peroxisomes. We found that DEPP1 (decidual protein induced by progesterone 1) is induced under hypoxia in a HIF-dependent manner and localizes inside mitochondria. DEPP1 is both necessary and sufficient for hypoxia-induced autophagy and triglyceride accumulation in cardiomyocytes ex vivo. DEPP1 loss increases cardiomyocyte survival in the setting of chronic HIF activation ex vivo, and whole-body Depp1 loss decreases cardiac dysfunction in hearts with chronic HIF activation caused by VHL loss in vivo. CONCLUSIONS Our findings identify DEPP1 as a key component in the cardiac remodeling that occurs with chronic ischemia.

更新日期：2024-06-17

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