Deletion of low molecular weight protein tyrosine phosphatase (Acp1) protects against stress-induced cardiomyopathy

作者：Wade Fallou; Quijada Pearl; Al Haffar Kamar Mohamed Adib; Awad Salma Mahmoud; Kunhi Muhammad; Toko Haruhiro; Marashly Qussay; Belhaj Karim; Zahid Israa; Al Mohanna Falah; Stanford Stephanie M; Alvarez Roberto; Liu Yingge; Colak Dilek; Jordan Maria C; Roos Kenneth P; Assiri Abdullah; Al Habeeb Waleed; Sussman Mark; Bottini Nunzio; Poizat Coralie^*

来源：Journal of Pathology, 2015, 237(4): 482-494.

DOI：10.1002/path.4594

• low molecular weight protein tyrosine phosphatase
• ACP1
• protein tyrosine phosphatase
• cardiac hypertrophy
• heart failure

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 CaMKII.. 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.

• 出版日期2015-12