HIF1α Represses Cell Stress Pathways to Allow Proliferation of Hypoxic Fetal Cardiomyocytes

Nuno Guimarães-Camboa; Jennifer Stowe; Ivy Aneas; Noboru Sakabe; Paola Cattaneo; Lindsay Henderson; Michael S Kilberg; Randall S Johnson; Ju Chen; Andrew D McCulloch; Marcelo A Nobrega; Sylvia M Evans; Alexander C Zambon

doi:10.1016/j.devcel.2015.04.021

HIF1α Represses Cell Stress Pathways to Allow Proliferation of Hypoxic Fetal Cardiomyocytes

Dev Cell. 2015 Jun 8;33(5):507-21. doi: 10.1016/j.devcel.2015.04.021. Epub 2015 May 28.

Authors

Affiliations

¹ Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Institute for Biomedical Sciences Abel Salazar and GABBA Graduate Program, University of Porto, Porto 4050-313, Portugal.
² Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
³ Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.
⁴ Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
⁵ Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
⁶ Department of Biochemistry and Molecular Biology, Shands Cancer Center and Center for Nutritional Sciences, University of Florida College of Medicine, Gainesville, FL 32160, USA.
⁷ Department of Physiology, Development and Neuroscience, University of Cambridge, CB2 3EG Cambridge, UK.
⁸ Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
⁹ Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: syevans@ucsd.edu.
¹⁰ Department of Biopharmaceutical Sciences, Keck Graduate Institute, Claremont, CA 91711, USA. Electronic address: azambon@kgi.edu.

Abstract

Transcriptional mediators of cell stress pathways, including HIF1α, ATF4, and p53, are key to normal development and play critical roles in disease, including ischemia and cancer. Despite their importance, mechanisms by which pathways mediated by these transcription factors interact with one another are not fully understood. In addressing the controversial role of HIF1α in cardiomyocytes (CMs) during heart development, we discovered a mid-gestational requirement for HIF1α for proliferation of hypoxic CMs, involving metabolic switching and a complex interplay among HIF1α, ATF4, and p53. Loss of HIF1α resulted in activation of ATF4 and p53, the latter inhibiting CM proliferation. Bioinformatic and biochemical analyses revealed unexpected mechanisms by which HIF1α intersects with ATF4 and p53 pathways. Our results highlight previously undescribed roles of HIF1α and interactions among major cell stress pathways that could be targeted to enhance proliferation of CMs in ischemia and may have relevance to other diseases, including cancer.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Activating Transcription Factor 4 / genetics
Activating Transcription Factor 4 / metabolism*
Animals
Biomarkers / metabolism
Blotting, Western
Cell Proliferation*
Cells, Cultured
Embryo, Mammalian / cytology*
Embryo, Mammalian / metabolism
Female
Fetus / cytology*
Fetus / metabolism
Flow Cytometry
Fluorescent Antibody Technique
Gene Expression Profiling
Hypoxia / physiopathology*
Hypoxia-Inducible Factor 1, alpha Subunit / physiology*
Immunoenzyme Techniques
Male
Mice
Mice, Knockout
Myocytes, Cardiac / cytology*
Myocytes, Cardiac / metabolism
Oligonucleotide Array Sequence Analysis
RNA, Messenger / genetics
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism*

Substances

Atf4 protein, mouse
Biomarkers
Hif1a protein, mouse
Hypoxia-Inducible Factor 1, alpha Subunit
RNA, Messenger
Tumor Suppressor Protein p53
Activating Transcription Factor 4

Associated data

GEO/GSE61209
GEO/GSE61247

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding