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.
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.
Authors: Randolph S Faustino; Anca Chiriac; Nicolas J Niederlander; Timothy J Nelson; Atta Behfar; Prasanna K Mishra; Slobodan Macura; Marek Michalak; Andre Terzic; Carmen Perez-Terzic Journal: Stem Cells Date: 2010-07 Impact factor: 6.277
Authors: Sarah C Hoelscher; Stefanie A Doppler; Martina Dreßen; Harald Lahm; Rüdiger Lange; Markus Krane Journal: J Thorac Dis Date: 2017-03 Impact factor: 2.895
Authors: Hui Yang; Wanqing Sun; Nanhu Quan; Lin Wang; Dongyang Chu; Courtney Cates; Quan Liu; Yang Zheng; Ji Li Journal: Biochem Pharmacol Date: 2016-03-22 Impact factor: 5.858
Authors: Chen Zhao; Hua Guo; Jingjing Li; Thomas Myint; William Pittman; Le Yang; Weimin Zhong; Robert J Schwartz; John J Schwarz; Harold A Singer; Michelle D Tallquist; Mingfu Wu Journal: Development Date: 2013-12-11 Impact factor: 6.868