Abstract 15317: Deletion of Low Molecular Weight Protein Tyrosine Phosphatase (Acp1) Protects Against Stress-induced Cardiomyopathy

Background: The low molecular weight protein tyrosine phosphatase (LMPTP), encoded by the ACP1 gene, is a ubiquitously expressed phosphatase whose in vivo function remains poorly understood. Genetic studies revealed an association between ACP1 and a variety of human cardiovascular disorders. However, evidence of a direct involvement of LMPTP in cardiac diseases is still lacking. Methodology: We generated the first mouse model of Lmptp deficiency and studied the response of the mice under basal condition or to long-term pressure overload using comprehensive experimental approaches such as q-PCR, siRNA technology, fluorescent microscopy and immuneprecipitation technique. Results: Acp1 -/- mice develop normally, and aging mice do not show any obvious signs of pathology in major tissues under basal condition. 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 post-natal stage, and increased in the adult mouse and human failing heart. Consistent with their protected phenotype, Acp1 -/- mice subjected to pressure overload hypertrophy have attenuated fibrosis and decreased expression of hypertrophic markers. Transcriptional profiling and analysis of molecular signaling shows that the resistance of Acp1 -/- mice to pathological cardiac stress correlates with marginal expression of fetal cardiac genes, increased insulin receptor beta phosphorylation and inactivation of CaMKIIδ pathway. Conclusion: Our data show that ablation of Lmptp inhibits pathological cardiac remodeling and suggest that inhibition of LMPTP may be of therapeutic relevance for the treatment of heart failure in human.