HIF1? Represses Cell Stress Pathways to Allow Proliferation of Hypoxic Fetal Cardiomyocytes

Transcriptional mediators of cell stress pathways, including HIF1?, 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 HIF1? in cardiomyocytes (CMs) during heart development, we discovered a mid-gestational requirement for HIF1? for proliferation of hypoxic CMs, involving metabolic switching anda complex interplay among HIF1?, ATF4, and p53. Loss of HIF1? resulted in activation of ATF4 andp53, the latter inhibiting CM proliferation. Bioinformatic and biochemical analyses revealed unexpected mechanisms by which HIF1? intersects with ATF4 and p53 pathways. Our results highlight previously undescribed roles of HIF1? 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.