title: The mammalian Ste20-like kinase 2 (Mst2) modulates stress-induced cardiac hypertrophy.
abstract: The Hippo signaling pathway has recently moved to center stage in cardiac research because of its key role in cardiomyocyte proliferation and regeneration of the embryonic and newborn heart. However, its role in the adult heart is incompletely understood. We investigate here the role of mammalian Ste20-like kinase 2 (Mst2), one of the central regulators of this pathway. Mst2(-/-) mice showed no alteration in cardiomyocyte proliferation. However, Mst2(-/-) mice exhibited a significant reduction of hypertrophy and fibrosis in response to pressure overload. Consistently, overexpression of MST2 in neonatal rat cardiomyocytes significantly enhanced phenylephrine-induced cellular hypertrophy. Mechanistically, Mst2 positively modulated the prohypertrophic Raf1-ERK1/2 pathway. However, activation of the downstream effectors of the Hippo pathway (Yes-associated protein) was not affected by Mst2 ablation. An initial genetic study in mitral valve prolapse patients revealed an association between a polymorphism in the human MST2 gene and adverse cardiac remodeling. These results reveal a novel role of Mst2 in stress-dependent cardiac hypertrophy and remodeling in the adult mouse and likely human heart.
authors.affiliation: From the Institute of Cardiovascular Sciences, University of Manchester and Manchester Academic Health Science Centre, Manchester M13 9PT, United Kingdom.
authors.forename: Min
authors.initials: M
authors.lastname: Zi
authors.affiliation: From the Institute of Cardiovascular Sciences, University of Manchester and Manchester Academic Health Science Centre, Manchester M13 9PT, United Kingdom.
authors.forename: Arfa
authors.initials: A
authors.lastname: Maqsood
authors.affiliation: From the Institute of Cardiovascular Sciences, University of Manchester and Manchester Academic Health Science Centre, Manchester M13 9PT, United Kingdom.
authors.forename: Sukhpal
authors.initials: S
authors.lastname: Prehar
authors.affiliation: From the Institute of Cardiovascular Sciences, University of Manchester and Manchester Academic Health Science Centre, Manchester M13 9PT, United Kingdom.
authors.forename: Tamer M A
authors.initials: TM
authors.lastname: Mohamed
authors.affiliation: From the Institute of Cardiovascular Sciences, University of Manchester and Manchester Academic Health Science Centre, Manchester M13 9PT, United Kingdom.
authors.forename: Riham
authors.initials: R
authors.lastname: Abou-Leisa
authors.affiliation: From the Institute of Cardiovascular Sciences, University of Manchester and Manchester Academic Health Science Centre, Manchester M13 9PT, United Kingdom.
authors.forename: Abigail
authors.initials: A
authors.lastname: Robertson
authors.affiliation: From the Institute of Cardiovascular Sciences, University of Manchester and Manchester Academic Health Science Centre, Manchester M13 9PT, United Kingdom.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Cartwright
authors.affiliation: the Department of Cardiology, South Manchester University Hospital and Manchester Academic Health Science Centre, Manchester M23 9LT, United Kingdom, and.
authors.forename: Simon G
authors.initials: SG
authors.lastname: Ray
authors.affiliation: the Department of Biological Sciences, National Creative Research Initiatives Center, Graduate School of Nanoscience and Technology (WCU), Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
authors.forename: Sangphil
authors.initials: S
authors.lastname: Oh
authors.affiliation: the Department of Biological Sciences, National Creative Research Initiatives Center, Graduate School of Nanoscience and Technology (WCU), Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
authors.forename: Dae-Sik
authors.initials: DS
authors.lastname: Lim
authors.affiliation: From the Institute of Cardiovascular Sciences, University of Manchester and Manchester Academic Health Science Centre, Manchester M13 9PT, United Kingdom.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Neyses
authors.affiliation: From the Institute of Cardiovascular Sciences, University of Manchester and Manchester Academic Health Science Centre, Manchester M13 9PT, United Kingdom, delvac.oceandy@manchester.ac.uk.
authors.forename: Delvac
authors.initials: D
authors.lastname: Oceandy
mesh_terms: D000818:Animals; D017209:Apoptosis; D006332:Cardiomegaly / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D049109:Cell Proliferation; D006801:Humans; D020287:In Situ Nick-End Labeling; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010656:Phenylephrine / Q000009:adverse effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D000090742:Serine-Threonine Kinase 3; D013312:Stress, Physiological; D000099317:Hippo Kinases
chemical_list: D010656:Phenylephrine; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D000090742:Serine-Threonine Kinase 3; C490818:Stk3 protein, mouse; D000099317:Hippo Kinases
keywords: Cardiac Hypertrophy; Cardiovascular Disease; Genetic Polymorphism; Signal Transduction; Transgenic Mice