Abstract：
UNASSIGNED: 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.
UNASSIGNED: 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 hearts and 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.
UNASSIGNED: 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.
UNASSIGNED: Our findings identify DEPP1 as a key component in the cardiac remodeling that occurs with chronic ischemia.
UNASSIGNED: 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 hearts and 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.
UNASSIGNED: 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.
UNASSIGNED: Our findings identify DEPP1 as a key component in the cardiac remodeling that occurs with chronic ischemia.
摘要：
■HIF（缺氧诱导因子）调节心脏功能的许多方面。我们和其他人先前表明，在小鼠模型中，心脏中的慢性HIF激活会表现出人类缺血性心肌病的多种特征，包括线粒体丢失,脂质积累，心脏收缩功能障碍.在某些设置中，HIF还导致过氧化物酶体的损失。How,机械上,HIF促进心脏功能障碍是一个悬而未决的问题。
■我们使用缺乏心脏pVHL（vonHippel-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，如自噬诱导和脂质积累。我们进行了免疫印迹试验,RNA测序，线粒体和过氧化物酶体自噬通量测量，以及心脏和分离心肌细胞的活细胞成像。我们在小鼠中使用CRISPR-Cas9基因编辑来验证慢性HIF激活背景下心脏功能障碍的新介质。
■我们确定了一种先前未知的途径，通过该途径，心脏HIF激活可促进线粒体和过氧化物酶体的丢失。我们发现DEPP1（孕酮1诱导的蜕膜蛋白）在缺氧下以HIF依赖性方式诱导并定位在线粒体内。DEPP1对于缺氧诱导的自噬和甘油三酸酯在离体心肌细胞中的积累既必要又充分。DEPP1丢失增加了体外慢性HIF激活的心肌细胞存活率，全身Depp1丢失可减少体内VHL丢失引起的慢性HIF激活心脏的心功能不全。
■我们的发现将DEPP1确定为慢性缺血发生的心脏重塑的关键组成部分。
■我们使用缺乏心脏pVHL（vonHippel-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，如自噬诱导和脂质积累。我们进行了免疫印迹试验,RNA测序，线粒体和过氧化物酶体自噬通量测量，以及心脏和分离心肌细胞的活细胞成像。我们在小鼠中使用CRISPR-Cas9基因编辑来验证慢性HIF激活背景下心脏功能障碍的新介质。
■我们确定了一种先前未知的途径，通过该途径，心脏HIF激活可促进线粒体和过氧化物酶体的丢失。我们发现DEPP1（孕酮1诱导的蜕膜蛋白）在缺氧下以HIF依赖性方式诱导并定位在线粒体内。DEPP1对于缺氧诱导的自噬和甘油三酸酯在离体心肌细胞中的积累既必要又充分。DEPP1丢失增加了体外慢性HIF激活的心肌细胞存活率，全身Depp1丢失可减少体内VHL丢失引起的慢性HIF激活心脏的心功能不全。
■我们的发现将DEPP1确定为慢性缺血发生的心脏重塑的关键组成部分。
