Deprivation of MKK7 in cardiomyocytes provokes heart failure in mice when exposed to pressure overload
Program in Molecular Medicine
Animals; Apoptosis; Cardiomegaly; Echocardiography; Heart Failure; Immunoblotting; In Situ Nick-End Labeling; MAP Kinase Kinase 7; Mice; Mice, Knockout; Myocytes, Cardiac; Polymerase Chain Reaction; *Pressure; Signal Transduction; Superoxides; Transforming Growth Factor beta
Biochemistry | Cell Biology | Cellular and Molecular Physiology | Molecular Biology
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 beta (TGF-beta) 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.
DOI of Published Version
J Mol Cell Cardiol. 2011 Apr;50(4):702-11. doi: 10.1016/j.yjmcc.2011.01.013. Epub 2011 Jan 31. Link to article on publisher's site
Journal of molecular and cellular cardiology
Liu, Wei; Zi, Min; Chi, Hongbo; Jin, Jiawei; Prehar, Sukhpal; Neyses, Ludwig; Cartwright, Elizabeth J.; Flavell, Richard A.; Davis, Roger J.; and Wang, Xin, "Deprivation of MKK7 in cardiomyocytes provokes heart failure in mice when exposed to pressure overload" (2011). Davis Lab Publications. 33.