Role of a Functional SNP of the Gene Coding Brain Serotonin Synthesis Rate-Limiting Enzyme Tph2 in Dilated Cardiomyopathy

Abstract

Brain serotonin dysfunction is involved in depression, which has been shown to increase the risk of death in heart failure (HF) patients. Tryptophan hydroxylase 2 (TPH2) expressed specifically in the central nervous system is involved in serotonin synthesis in the brain as a rate-limiting enzyme. Inbred mice have a functional single nucleotide polymorphism (SNP) C1473G in Tph2, with the Tph2 activity being lower in BALB/c strain with G/G allele than in C57BL/6 mice with C/C allele. In this study, we examined the role of this SNP in the disease phenotype of knockin mice with a dilated cardiomyopathy (DCM)-causing mutation ΔK210 in cardiac troponin T (cTnT) by creating single-gene congenic strain with Tph2 1473C/C or G/G allele. The ΔK210-cTnT DCM mice on C57BL/6 background frequently suffered from sudden cardiac death (SCD) with no heart failure symptoms, whereas the ΔK210-cTnT DCM mice on BALB/c background mostly died of congestive HF instead of SCD. Introduction of Tph2 1473G/G allele into C57BL/6 background DCM mice caused congestive HF death while decreasing SCD and extending the life expectancy. On the other hand, introduction of Tph2 1473C/C allele into BALB/c background DCM mice caused SCD while decreasing congestive HF death and shortening the life expectancy. These results strongly suggest that brain serotonin function plays an important role in the disease phenotype of DCM.