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Induction of DEPP1 by HIF Mediates Multiple Hallmarks of Ischemic Cardiomyopathy
Gregory A Wyant1,2, Qinqin Jiang1, Madhu Singh2
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA (G.A.W., Q.J., C.L., W.G.K.).
Insights
Hypoxia-inducible factor (HIF) activation in the heart causes cardiac dysfunction. We discovered DEPP1 mediates this by promoting mitochondrial and peroxisomal loss, identifying it as a therapeutic target for ischemic cardiomyopathy.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Cellular Physiology
Background:
- Hypoxia-inducible factor (HIF) critically regulates cardiac function.
- Chronic HIF activation in the heart mimics ischemic cardiomyopathy features like mitochondrial loss and dysfunction.
- The precise mechanisms by which HIF drives cardiac dysfunction remain unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms by which chronic HIF activation induces cardiac dysfunction.
- To identify novel mediators of HIF-induced cardiac remodeling and dysfunction.
Main Methods:
- Utilized mice with cardiac-specific pVHL deficiency to model chronic HIF activation.
- Employed immunoblotting, RNA sequencing, autophagy flux assays, and live cell imaging.
- Applied CRISPR-Cas9 gene editing to validate key molecular players in vivo.
Main Results:
- Identified a novel pathway where HIF induces DEPP1 (decidual protein induced by progesterone 1).
- DEPP1 localizes to mitochondria and is essential for hypoxia-induced autophagy and lipid accumulation in cardiomyocytes.
- DEPP1 deficiency enhances cardiomyocyte survival and mitigates cardiac dysfunction in vivo.
Conclusions:
- DEPP1 is a critical mediator of cardiac remodeling and dysfunction under chronic hypoxic conditions.
- Targeting DEPP1 presents a potential therapeutic strategy for 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.
