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Deletion of low molecular weight protein tyrosine phosphatase ( Acp1 ) protects against stress‐induced cardiomyopathy
Author(s) -
Wade Fallou,
Quijada Pearl,
AlHaffar Kamar Mohamed Adib,
Awad Salma Mahmoud,
Kunhi Muhammad,
Toko Haruhiro,
Marashly Qussay,
Belhaj Karim,
Zahid Israa,
AlMohanna Falah,
Stanford Stephanie M,
Alvarez Roberto,
Liu Yingge,
Colak Dilek,
Jordan Maria C,
Roos Kenneth P,
Assiri Abdullah,
AlHabeeb Waleed,
Sussman Mark,
Bottini Nunzio,
Poizat Coralie
Publication year - 2015
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4594
Subject(s) - pressure overload , biology , phosphatase , protein tyrosine phosphatase , heart failure , endocrinology , knockout mouse , cardiac function curve , cardiomyopathy , gene expression , medicine , muscle hypertrophy , phosphorylation , gene , microbiology and biotechnology , biochemistry , cardiac hypertrophy
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. © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.