title: Deprivation of MKK7 in cardiomyocytes provokes heart failure in mice when exposed to pressure overload.
abstract: There is little doubt that members of mitogen-activated protein kinase (MAPK) families play key roles in the transition from adaptive hypertrophic remodeling to heart failure. Mitogen-activated protein kinase kinase 7 (MKK7) is a critical component of stress-activated MAP kinase signaling pathway. The role of MKK7 plays in mediating cardiac remodeling in response to load stress has yet to be defined. Herein, we investigate the role of MKK7 in regulating cardiac remodeling in response to pressure overload. We generated and examined the phenotype of mice with cardiomyocyte-specific deletion of the mkk7 gene (MKK7(cko)). Following one week of pressure overload, MKK7(cko) mice exhibited characteristic phenotypes of heart failure evidenced by deterioration in ventricular function and pulmonary congestion. Cell death assays revealed an increased prevalence of cardiomyocyte apoptosis in the MKK7(cko) heart, in which elevated p53 levels and attenuated expression of manganese superoxide dismutase (MnSOD) were found. Moreover, extensive interstitial fibrosis was discovered in the knockout heart likely attributable to upregulation of transforming growth factor β (TGF-β) signaling. These results reveal an essential role of MKK7 in cardiomyocytes for protecting the heart from hypertrophic insults thereby preventing the transition to heart failure.
authors.affiliation: Faculty of Life Sciences, The University of Manchester, Manchester, M13 9NT, UK.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Min
authors.initials: M
authors.lastname: Zi
authors.forename: Hongbo
authors.initials: H
authors.lastname: Chi
authors.forename: Jiawei
authors.initials: J
authors.lastname: Jin
authors.forename: Sukhpal
authors.initials: S
authors.lastname: Prehar
authors.forename: Ludwig
authors.initials: L
authors.lastname: Neyses
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Cartwright
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Davis
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D004452:Echocardiography; D006333:Heart Failure / Q000235:genetics / Q000503:physiopathology*; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D048688:MAP Kinase Kinase 7 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D016133:Polymerase Chain Reaction; D011312:Pressure; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013481:Superoxides / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D016212:Transforming Growth Factor beta; D013481:Superoxides; D048688:MAP Kinase Kinase 7; C482570:Map2k7 protein, mouse