title: Capacity for resolution of Ras-MAPK-initiated early pathogenic myocardial hypertrophy modeled in mice.
abstract: Activation of Ras signaling in cardiomyocytes has been linked to pathogenic myocardial hypertrophy progression and subsequent heart failure. Whether cardiomyopathy can regress once initiated needs to be established more fully. A 'tet-off' system was used to regulate expression of H-Ras-G12V in myocardium to examine whether Ras-induced pathogenic myocardial hypertrophy could resolve after removal of Ras signaling in vivo. Ras activation at weaning for 2 wk caused hypertrophy, whereas activation for 4 to 8 wk led to cardiomyopathy and heart failure. Discontinuing H-Ras-G12V transgene expression after cardiomyopathy onset led to improved survival and cardiomyopathy lesion scores, with reduced heart:body weight ratios, demonstrating the reversibility of early pathogenic hypertrophy. Activation of Ras and downstream ERK 1/2 was associated with elevated expression of proliferating cell nuclear antigen and cyclins B1 and D1, indicating cell-cycle activation and reentry. Coordinate elevation of broad-spectrum cyclin-dependent kinase inhibitors (p21, p27, and p57) and Tyr15 phosphorylation of cdc2 signified the activation of cell-cycle checkpoints; absence of cell-cycle completion and cardiomyocyte replication were documented by using immunohistochemistry for mitosis and cytokinesis markers. After resolution of cardiomyopathy, cell-cycle activators and inhibitors examined returned to basal levels, a change that we interpreted as exit from the cell cycle. Cardiac cell-cycle regulation plays a role in recovery from pathogenic hypertrophy. The model we present provides a means to further explore the underlying mechanisms governing cell-cycle capacity in cardiomyocytes, as well as progression and regression of pathogenic cardiomyocyte hypertrophy.
authors.affiliation: Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Bih-Rong
authors.initials: BR
authors.lastname: Wei
authors.forename: Philip L
authors.initials: PL
authors.lastname: Martin
authors.forename: Shelley B
authors.initials: SB
authors.lastname: Hoover
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Spehalski
authors.forename: Mia
authors.initials: M
authors.lastname: Kumar
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Hoenerhoff
authors.forename: Julian
authors.initials: J
authors.lastname: Rozenberg
authors.forename: Charles
authors.initials: C
authors.lastname: Vinson
authors.forename: R Mark
authors.initials: RM
authors.lastname: Simpson
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D006332:Cardiomegaly / Q000201:enzymology / Q000378:metabolism*; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009206:Myocardium / Q000473:pathology; D019076:Transgenes; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D009320:Atrial Natriuretic Factor; D048052:Mitogen-Activated Protein Kinase 3; D018631:ras Proteins