title: Notch-independent RBPJ controls angiogenesis in the adult heart.
abstract: Increasing angiogenesis has long been considered a therapeutic target for improving heart function after injury such as acute myocardial infarction. However, gene, protein and cell therapies to increase microvascularization have not been successful, most likely because the studies failed to achieve regulated and concerted expression of pro-angiogenic and angiostatic factors needed to produce functional microvasculature. Here, we report that the transcription factor RBPJ is a homoeostatic repressor of multiple pro-angiogenic and angiostatic factor genes in cardiomyocytes. RBPJ controls angiogenic factor gene expression independently of Notch by antagonizing the activity of hypoxia-inducible factors (HIFs). In contrast to previous strategies, the cardiomyocyte-specific deletion of Rbpj increased microvascularization of the heart without adversely affecting cardiac structure or function even into old age. Furthermore, the loss of RBPJ in cardiomyocytes increased hypoxia tolerance, improved heart function and decreased pathological remodelling after myocardial infarction, suggesting that inhibiting RBPJ might be therapeutic for ischaemic injury.
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, USA.|Department of Bioengineering, Jacobs School of Engineering, University of California, San Diego, La Jolla, California 92093 USA.
authors.forename: Ramón
authors.initials: R
authors.lastname: Díaz-Trelles
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, USA.|Department of Bioengineering, Jacobs School of Engineering, University of California, San Diego, La Jolla, California 92093 USA.|Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, California 92093 USA.
authors.forename: Maria Cecilia
authors.initials: MC
authors.lastname: Scimia
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, USA.|Department of Bioengineering, Jacobs School of Engineering, University of California, San Diego, La Jolla, California 92093 USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Bushway
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, USA.
authors.forename: Danh
authors.initials: D
authors.lastname: Tran
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Monosov
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Monosov
authors.affiliation: Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, California 92093 USA.
authors.forename: Kirk
authors.initials: K
authors.lastname: Peterson
authors.affiliation: Departments of Medicine, Developmental Biology and Biomedical Engineering, Washington University, St Louis, Missouri 63110 USA.
authors.forename: Stacey
authors.initials: S
authors.lastname: Rentschler
authors.affiliation: Department of Bioengineering, Jacobs School of Engineering, University of California, San Diego, La Jolla, California 92093 USA.
authors.forename: Pedro
authors.initials: P
authors.lastname: Cabrales
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, California 94305 USA.
authors.forename: Pilar
authors.initials: P
authors.lastname: Ruiz-Lozano
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, USA.|Department of Bioengineering, Jacobs School of Engineering, University of California, San Diego, La Jolla, California 92093 USA.|Stanford Cardiovascular Institute and Department of Medicine, Stanford University, Stanford, California 94305, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Mercola
mesh_terms: D000818:Animals; D003331:Coronary Vessels / Q000254:growth & development*; D005260:Female; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000502:physiology*; D008297:Male; D051379:Mice; D055806:Microvessels / Q000254:growth & development; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D019899:Paracrine Communication
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497571:Rbpj protein, mouse