RRC ID 6014
Author Kratsios P, Catela C, Salimova E, Huth M, Berno V, Rosenthal N, Mourkioti F.
Title Distinct roles for cell-autonomous Notch signaling in cardiomyocytes of the embryonic and adult heart.
Journal Circ. Res.
Abstract RATIONALE:The Notch signaling pathway is important for cell-cell communication that controls tissue formation and homeostasis during embryonic and adult life, but the precise cell targets of Notch signaling in the mammalian heart remain poorly defined.
OBJECTIVE:To investigate the functional role of Notch signaling in the cardiomyocyte compartment of the embryonic and adult heart.
METHODS AND RESULTS:Here, we report that either conditional overexpression of Notch1 intracellular domain (NICD1) or selective silencing of Notch signaling in the embryonic cardiomyocyte compartment results in developmental defects and perinatal lethality. In contrast, augmentation of endogenous Notch reactivation after myocardial infarction in the adult, either by inducing cardiomyocyte-specific Notch1 transgene expression or by intramyocardial delivery of a Notch1 pseudoligand, increases survival rate, improves cardiac functional performance, and minimizes fibrosis, promoting antiapoptotic and angiogenic mechanisms.
CONCLUSIONS:These results reveal a strict requirement for cell-autonomous modulation of Notch signaling during heart morphogenesis, and illustrate how the same signaling pathway that promotes congenital heart defects when perturbed in the embryo can be therapeutically redeployed for the treatment of adult myocardial damage.
Volume 106(3)
Pages 559-72
Published 2010-2-19
DOI 10.1161/CIRCRESAHA.109.203034
PII CIRCRESAHA.109.203034
PMID 20007915
MeSH Age Factors Animals Cell Differentiation Collateral Circulation / physiology Fetal Heart / cytology Gene Expression Regulation Heart Defects, Congenital / genetics Heart Defects, Congenital / pathology Male Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Morphogenesis / genetics Myocardial Infarction / pathology Myocardial Infarction / therapy Myocardium / cytology Myocytes, Cardiac / physiology* Nuclear Proteins / deficiency Nuclear Proteins / genetics Nuclear Proteins / physiology Protein Structure, Tertiary Receptor, Notch1 / biosynthesis Receptor, Notch1 / genetics Receptor, Notch1 / physiology* Recombinant Fusion Proteins / biosynthesis Recombinant Fusion Proteins / genetics Regeneration Signal Transduction / drug effects Transcription Factors / deficiency Transcription Factors / genetics Transcription Factors / physiology
IF 15.862
Times Cited 47
WOS Category CARDIAC & CARDIOVASCULAR SYSTEMS PERIPHERAL VASCULAR DISEASE HEMATOLOGY
Resource
Mice CAG-CAT-Notch1