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

ABSTRACT: 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 and a complex interplay among HIF1?, ATF4, and p53. Loss of HIF1? resulted in activation of ATF4 and p53, 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.

SUBMITTER: Guimaraes-Camboa N

PROVIDER: S-EPMC4509618 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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

Guimarães-Camboa Nuno N Stowe Jennifer J Aneas Ivy I Sakabe Noboru N Cattaneo Paola P Henderson Lindsay L Kilberg Michael S MS Johnson Randall S RS Chen Ju J McCulloch Andrew D AD Nobrega Marcelo A MA Evans Sylvia M SM Zambon Alexander C AC

Developmental cell 20150528 5

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 hy ...[more]

PMID: 26028220

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Project description:RATIONALE:Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are a readily available, robustly reproducible, and physiologically appropriate human cell source for cardiac disease modeling, drug discovery, and toxicity screenings in vitro. However, unlike adult myocardial cells in vivo, hPSC-CMs cultured in vitro maintain an immature metabolic phenotype, where majority of ATP is produced through aerobic glycolysis instead of oxidative phosphorylation in the mitochondria. Little is known about the underlying signaling pathways controlling hPSC-CMs' metabolic and functional maturation. OBJECTIVE:To define the molecular pathways controlling cardiomyocytes' metabolic pathway selections and improve cardiomyocyte metabolic and functional maturation. METHODS AND RESULTS:We cultured hPSC-CMs in different media compositions including glucose-containing media, glucose-containing media supplemented with fatty acids, and glucose-free media with fatty acids as the primary carbon source. We found that cardiomyocytes cultured in the presence of glucose used primarily aerobic glycolysis and aberrantly upregulated HIF1? (hypoxia-inducible factor 1?) and its downstream target lactate dehydrogenase A. Conversely, glucose deprivation promoted oxidative phosphorylation and repressed HIF1?. Small molecule inhibition of HIF1? or lactate dehydrogenase A resulted in a switch from aerobic glycolysis to oxidative phosphorylation. Likewise, siRNA inhibition of HIF1? stimulated oxidative phosphorylation while inhibiting aerobic glycolysis. This metabolic shift was accompanied by an increase in mitochondrial content and cellular ATP levels. Furthermore, functional gene expressions, sarcomere length, and contractility were improved by HIF1?/lactate dehydrogenase A inhibition. CONCLUSIONS:We show that under standard culture conditions, the HIF1?-lactate dehydrogenase A axis is aberrantly upregulated in hPSC-CMs, preventing their metabolic maturation. Chemical or siRNA inhibition of this pathway results in an appropriate metabolic shift from aerobic glycolysis to oxidative phosphorylation. This in turn improves metabolic and functional maturation of hPSC-CMs. These findings provide key insight into molecular control of hPSC-CMs' metabolism and may be used to generate more physiologically mature cardiomyocytes for drug screening, disease modeling, and therapeutic purposes.

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

Publications

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

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