Reference - Detail
|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.|
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.
|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|
|WOS Category||CARDIAC & CARDIOVASCULAR SYSTEMS PERIPHERAL VASCULAR DISEASE HEMATOLOGY|