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

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&agr; protein. Mice lacking HIF1&agr; in ventricular cardiomyocytes exhibit aborted development at looping morphogenesis and embryonic lethality between E11.0 to E12.0. Intriguingly, HIF1&agr;-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&agr; in vivo. Thus, hypoxia signaling controls cardiac development through HIF1&agr;-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.

[1]  E. Elion,et al.  Constructing Recombinant DNA Molecules by PCR , 2007, Current protocols in molecular biology.

[2]  M. Bennett,et al.  Pan‐myocardial expression of Cre recombinase throughout mouse development , 2007, Genesis.

[3]  Yiming Wu,et al.  Targeted deletion of titin N2B region leads to diastolic dysfunction and cardiac atrophy , 2007, Proceedings of the National Academy of Sciences.

[4]  S. Dunwoodie.  Combinatorial signaling in the heart orchestrates cardiac induction, lineage specification and chamber formation. , 2007, Seminars in cell & developmental biology.

[5]  B. Erdmann,et al.  M line–deficient titin causes cardiac lethality through impaired maturation of the sarcomere , 2006, The Journal of cell biology.

[6]  Wolfgang A Linke,et al.  Plasticity of cardiac titin/connectin in heart development , 2006, Journal of Muscle Research & Cell Motility.

[7]  G. Cox,et al.  Dilated cardiomyopathy in the nmd mouse: transgenic rescue and QTLs that improve cardiac function and survival. , 2005, Human molecular genetics.

[8]  G. Camenisch,et al.  Integration of Oxygen Signaling at the Consensus HRE , 2005, Science's STKE.

[9]  Thomas Sejersen,et al.  The Kinase Domain of Titin Controls Muscle Gene Expression and Protein Turnover , 2005, Science.

[10]  S. Marcato,et al.  A new L1446P mutation is responsible for impaired von Willebrand factor synthesis, structure, and function. , 2004, The Journal of laboratory and clinical medicine.

[11]  E. Dodou,et al.  Mef2c is a direct transcriptional target of ISL1 and GATA factors in the anterior heart field during mouse embryonic development , 2004, Development.

[12]  E. Ehler,et al.  Sequential myofibrillar breakdown accompanies mitotic division of mammalian cardiomyocytes , 2004, Journal of Cell Science.

[13]  R. Johnson,et al.  Cardiac myocyte‐specific HIF‐1α deletion alters vascularization, energy availability, calcium flux, and contractility in the normoxic heart , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[14]  Kan Ding,et al.  Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1−/− mice , 2003, Nature Genetics.

[15]  P. Carmeliet,et al.  Cardia bifida, defective heart development and abnormal neural crest migration in embryos lacking hypoxia-inducible factor-1alpha. , 2003, Cardiovascular research.

[16]  A. Moorman,et al.  Cardiac chamber formation: development, genes, and evolution. , 2003, Physiological reviews.

[17]  H. Moch,et al.  Chemokine receptor CXCR4 downregulated by von Hippel–Lindau tumour suppressor pVHL , 2003, Nature.

[18]  S. Nishikawa,et al.  Chamber‐specific differentiation of Nkx2.5‐positive cardiac precursor cells from murine embryonic stem cells , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[19]  L. Poellinger,et al.  Identification of Residues Critical for Regulation of Protein Stability and the Transactivation Function of the Hypoxia-inducible Factor-1α by the von Hippel-Lindau Tumor Suppressor Gene Product* , 2003, The Journal of Biological Chemistry.

[20]  D. Turnbull,et al.  Onset of Cardiac Function During Early Mouse Embryogenesis Coincides With Entry of Primitive Erythroblasts Into the Embryo Proper , 2003, Circulation research.

[21]  Till Acker,et al.  Loss of HIF-2α and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice , 2002, Nature Medicine.

[22]  T Kobayashi,et al.  Hypoxia in cartilage: HIF-1alpha is essential for chondrocyte growth arrest and survival. , 2001, Genes & development.

[23]  J. Schmitt,et al.  A Murine Model of Holt-Oram Syndrome Defines Roles of the T-Box Transcription Factor Tbx5 in Cardiogenesis and Disease , 2001, Cell.

[24]  Ryozo Nagai,et al.  Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation , 2001, Nature Genetics.

[25]  H. Chung,et al.  Determination of hypoxic region by hypoxia marker in developing mouse embryos in vivo: A possible signal for vessel development , 2001, Developmental dynamics : an official publication of the American Association of Anatomists.

[26]  M. Gertsenstein,et al.  Placental cell fates are regulated in vivo by HIF-mediated hypoxia responses. , 2000, Genes & development.

[27]  J. M. Arbeit,et al.  Hypoxia-inducible Factor-1α Is a Positive Factor in Solid Tumor Growth , 2000 .

[28]  E. Ehler,et al.  A Novel Marker for Vertebrate Embryonic Heart, the EH-myomesin Isoform* , 2000, The Journal of Biological Chemistry.

[29]  J. Palis,et al.  Development of erythroid and myeloid progenitors in the yolk sac and embryo proper of the mouse. , 1999, Development.

[30]  A. Giaccia,et al.  Hypoxic microenvironment within an embryo induces apoptosis and is essential for proper morphological development. , 1999, Teratology.

[31]  R. Hammer,et al.  The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development. , 1998, Genes & development.

[32]  L. Huang,et al.  Regulation of hypoxia-inducible factor 1α is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway , 1998 .

[33]  Jessica Lo,et al.  HIF‐1α is required for solid tumor formation and embryonic vascularization , 1998 .

[34]  K. Chien,et al.  Ventricular muscle-restricted targeting of the RXRalpha gene reveals a non-cell-autonomous requirement in cardiac chamber morphogenesis. , 1998, Development.

[35]  M. Gassmann,et al.  Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. , 1998, Genes & development.

[36]  C. Bucana,et al.  Control of mouse cardiac morphogenesis and myogenesis by transcription factor MEF2C. , 1997, Science.

[37]  E. Olson,et al.  Requirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis. , 1997, Genes & development.

[38]  K. Chien,et al.  Positional specification of ventricular myosin light chain 2 expression in the primitive murine heart tube. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[39]  P. Carmeliet,et al.  Loss of HIF-2α and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice , 2002, Nature Medicine.

[40]  R. Rickert,et al.  Hypoxia-Inducible Factor 1 (cid:2) Is Essential for Cell Cycle Arrest during Hypoxia , 2002 .

[41]  J. M. Arbeit,et al.  Hypoxia-inducible factor-1alpha is a positive factor in solid tumor growth. , 2000, Cancer research.

[42]  W. MacLellan,et al.  Genetic dissection of cardiac growth control pathways. , 2000, Annual review of physiology.

[43]  Philippe Soriano.  Generalized lacZ expression with the ROSA26 Cre reporter strain , 1999, Nature Genetics.

[44]  H. Ryan,et al.  HIF-1 alpha is required for solid tumor formation and embryonic vascularization. , 1998, The EMBO journal.

[45]  E. Dodou,et al.  Mef 2 c is a direct transcriptional target of ISL 1 and GATA factors in the anterior heart field during mouse embryonic development , 2022 .