title: Deletion of low molecular weight protein tyrosine phosphatase (Acp1) protects against stress-induced cardiomyopathy.
abstract: The low molecular weight protein tyrosine phosphatase (LMPTP), encoded by the ACP1 gene, is a ubiquitously expressed phosphatase whose in vivo function in the heart and in cardiac diseases remains unknown. To investigate the in vivo role of LMPTP in cardiac function, we generated mice with genetic inactivation of the Acp1 locus and studied their response to long-term pressure overload. Acp1(-/-) mice develop normally and ageing mice do not show pathology in major tissues under basal conditions. However, Acp1(-/-) mice are strikingly resistant to pressure overload hypertrophy and heart failure. Lmptp expression is high in the embryonic mouse heart, decreased in the postnatal stage, and increased in the adult mouse failing heart. We also show that LMPTP expression increases in end-stage heart failure in humans. Consistent with their protected phenotype, Acp1(-/-) mice subjected to pressure overload hypertrophy have attenuated fibrosis and decreased expression of fibrotic genes. Transcriptional profiling and analysis of molecular signalling show that the resistance of Acp1(-/-) mice to pathological cardiac stress correlates with marginal re-expression of fetal cardiac genes, increased insulin receptor beta phosphorylation, as well as PKA and ephrin receptor expression, and inactivation of the CaMKIIδ pathway. Our data show that ablation of Lmptp inhibits pathological cardiac remodelling and suggest that inhibition of LMPTP may be of therapeutic relevance for the treatment of human heart failure.
authors.affiliation: Cardiovascular Research Program, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Fallou
authors.initials: F
authors.lastname: Wade
authors.affiliation: San Diego State University, Department of Biology, 5500 Campanile Drive, San Diego, CA, USA.
authors.forename: Pearl
authors.initials: P
authors.lastname: Quijada
authors.affiliation: Cardiovascular Research Program, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Kamar Mohamed Adib
authors.initials: KM
authors.lastname: Al-Haffar
authors.affiliation: Cardiovascular Research Program, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Salma Mahmoud
authors.initials: SM
authors.lastname: Awad
authors.affiliation: Cardiovascular Research Program, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Kunhi
authors.affiliation: San Diego State University, Department of Biology, 5500 Campanile Drive, San Diego, CA, USA.
authors.forename: Haruhiro
authors.initials: H
authors.lastname: Toko
authors.affiliation: College of Medicine and Health Sciences, Al-Faisal University, Riyadh, Saudi Arabia.
authors.forename: Qussay
authors.initials: Q
authors.lastname: Marashly
authors.affiliation: College of Medicine and Health Sciences, Al-Faisal University, Riyadh, Saudi Arabia.
authors.forename: Karim
authors.initials: K
authors.lastname: Belhaj
authors.affiliation: Cardiovascular Research Program, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Israa
authors.initials: I
authors.lastname: Zahid
authors.affiliation: Department of Comparative Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Falah
authors.initials: F
authors.lastname: Al-Mohanna
authors.affiliation: Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA, USA.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Stanford
authors.affiliation: San Diego State University, Department of Biology, 5500 Campanile Drive, San Diego, CA, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Alvarez
authors.affiliation: USC Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
authors.forename: Yingge
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Biostatistics and Scientific Computing, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Dilek
authors.initials: D
authors.lastname: Colak
authors.affiliation: Department of Physiology, David Geffen School of Medicine at UCLA, 10833 LeConte Avenue, Los Angeles, CA, USA.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Jordan
authors.affiliation: Department of Physiology, David Geffen School of Medicine at UCLA, 10833 LeConte Avenue, Los Angeles, CA, USA.
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Roos
authors.affiliation: Department of Comparative Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Assiri
authors.affiliation: King Saud University, Riyadh, Saudi Arabia.
authors.forename: Waleed
authors.initials: W
authors.lastname: Al-Habeeb
authors.affiliation: San Diego State University, Department of Biology, 5500 Campanile Drive, San Diego, CA, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Sussman
authors.affiliation: Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA, USA.|USC Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
authors.forename: Nunzio
authors.initials: N
authors.lastname: Bottini
authors.affiliation: Cardiovascular Research Program, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.|San Diego State University, Department of Biology, 5500 Campanile Drive, San Diego, CA, USA.
authors.forename: Coralie
authors.initials: C
authors.lastname: Poizat
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D006333:Heart Failure / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051381:Rats; D054549:Takotsubo Cardiomyopathy / Q000378:metabolism*
chemical_list: D011518:Proto-Oncogene Proteins; C490429:ACP1 protein, human; C490428:Acp1 protein, mouse; D017027:Protein Tyrosine Phosphatases
keywords: ACP1; cardiac hypertrophy; heart failure; low molecular weight protein tyrosine phosphatase; protein tyrosine phosphatase