title: Targeted deletion of ERK2 in cardiomyocytes attenuates hypertrophic response but provokes pathological stress induced cardiac dysfunction.
abstract: Mitogen-activated protein kinases (MAPKs) are involved in the regulation of cardiac hypertrophy and myocyte survival. Extracellular signal regulated protein kinase 1 and 2 (ERK1/2) are key components in the MAPK signaling pathways. Dysfunction of ERK1/2 in congenital heart diseases (Noonan syndrome and LEOPARD syndrome) leads to cardiac hypertrophy. ERK2 contributes 70% of protein content to total ERK1/2 content in myocardium; however, the specific role of ERK2 in regulating cardiac hypertrophy is yet to be further defined. To investigate the specific role of ERK2 played in the cardiomyocytes, we generated and examined mice with cardiomyocyte-specific deletion of the erk2 gene (ERK2(cko) mice). Following short-term pathological hypertrophic stresses, the mutant mice showed attenuated hypertrophic remodeling characterized by a blunted increase in the cross-sectional area of individual myocytes, downregulation of hypertrophic foetal gene markers (ANP and BNP), and less interstitial fibrosis. However, increased cardiomyocyte apoptosis was observed. Upon prolonged stimulation, ERK2(cko) mice developed deterioration in cardiac function. However, absence of ERK2 did not affect physiological hypertrophy induced by 4weeks of swimming exercise. These results revealed an essential role for ERK2 in cardiomyocytes in the development of pathological hypertrophic remodeling and resistance to cell death.
authors.affiliation: Faculty of Life Sciences, The University of Manchester, Manchester M13 9NT, UK.
authors.forename: Susanne
authors.initials: S
authors.lastname: Ulm
authors.affiliation: Faculty of Life Sciences, The University of Manchester, Manchester M13 9NT, UK. Electronic address: wei.liu-2@manchester.ac.uk.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Faculty of Medical and Human Sciences, The University of Manchester, Manchester M13 9NT, UK.
authors.forename: Min
authors.initials: M
authors.lastname: Zi
authors.affiliation: Faculty of Life Sciences, The University of Manchester, Manchester M13 9NT, UK.
authors.forename: Hoyee
authors.initials: H
authors.lastname: Tsui
authors.affiliation: Faculty of Life Sciences, The University of Manchester, Manchester M13 9NT, UK.
authors.forename: Sanjoy K
authors.initials: SK
authors.lastname: Chowdhury
authors.affiliation: Aging Neuroscience Research Team, Tokyo Metropolitan Institute of Gerontology, Itabashi, Tokyo 173-0015, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Endo
authors.affiliation: Department of Anesthesiology, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Satoh
authors.affiliation: Faculty of Medical and Human Sciences, The University of Manchester, Manchester M13 9NT, UK.
authors.forename: Sukhpal
authors.initials: S
authors.lastname: Prehar
authors.affiliation: Faculty of Life Sciences, The University of Manchester, Manchester M13 9NT, UK.
authors.forename: Ruoxi
authors.initials: R
authors.lastname: Wang
authors.affiliation: Faculty of Medical and Human Sciences, The University of Manchester, Manchester M13 9NT, UK.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Cartwright
authors.affiliation: Faculty of Life Sciences, The University of Manchester, Manchester M13 9NT, UK.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D005355:Fibrosis; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000172:deficiency* / Q000235:genetics; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D013312:Stress, Physiological; D013550:Swimming
chemical_list: D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: Apoptosis; Cardiac hypertrophy; Genetically modified mice; Interstitial fibrosis; Signal transduction