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(Circulation Research. 2008;103:1139.)
© 2008 American Heart Association, Inc.

Molecular Medicine

Essential Role of Developmentally Activated Hypoxia-Inducible Factor 1 for Cardiac Morphogenesis and Function

Jaya Krishnan, Preeti Ahuja^*, Sereina Bodenmann^*, Don Knapik, Evelyne Perriard, Wilhelm Krek, Jean-Claude Perriard

From the Institute of Cell Biology (J.K., P.A., S.B., E.P., W.K., J.-C.P.), Eidgenössische Technische Hochschule, Zürich, Switzerland; and VisualSonics BV (D.K.), Amsterdam, The Netherlands. Present address for P.A.: Department of Medicine and Physiology, School of Medicine, University of California, Los Angeles. Present address for S.B.: Institute of Pharmacology and Toxicology, University of Zurich, Switzerland.

Correspondence to Wilhelm Krek, ETH Zurich, Institute of Cell Biology, Schafmattstrasse 18, Zurich 8093, Switzerland. E-mail wilhelm.krek{at}cell.biol.ethz.ch

Development of the mammalian heart is governed by precisely orchestrated interactions between signaling pathways integrating environmental cues and a core cardiac transcriptional network that directs differentiation, growth and morphogenesis. Here we report that in mice, at about embryonic day (E)8.5 to E10.0, cardiac development proceeds in an environment that is hypoxic and characterized by high levels of hypoxia-inducible factor (HIF)1 protein. Mice lacking HIF1 in ventricular cardiomyocytes exhibit aborted development at looping morphogenesis and embryonic lethality between E11.0 to E12.0. Intriguingly, HIF1-deficient hearts display reduced expression of the core cardiac transcription factors Mef2C and Tbx5 and of titin, a giant protein that serves as a template for the assembly and organization of the sarcomere. Chromatin immunoprecipitation experiments revealed that Mef2C, Tbx5, and titin are direct target genes of HIF1 in vivo. Thus, hypoxia signaling controls cardiac development through HIF1-mediated transcriptional regulation of key components of myofibrillogenesis and the cardiac transcription factor network, thereby providing a mechanistic basis of how heart development, morphogenesis, and function is coupled to low oxygen tension during early embryogenesis.

Key Words: cardiac development • hypoxia • transcription • myofibrillogenesis • HIF1

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