title: Role of brain serotonin dysfunction in the pathophysiology of congestive heart failure.
abstract: Inherited or non-inherited dilated cardiomyopathy (DCM) patients develop varied disease phenotypes leading to death after developing congestive heart failure (HF) or sudden death with mild or no overt HF symptoms, suggesting that environmental and/or genetic factors may modify the disease phenotype of DCM. In this study, we sought to explore unknown genetic factors affecting the disease phenotype of monogenic inherited human DCM. Knock-in mice bearing a sarcomeric protein mutation that causes DCM were created on different genetic backgrounds; BALB/c and C57Bl/6. DCM mice on the BALB/c background showed cardiac enlargement and systolic dysfunction and developed congestive HF before died. In contrast, DCM mice on the C57Bl/6 background developed no overt HF symptoms and died suddenly, although they showed considerable cardiac enlargement and systolic dysfunction. BALB/c mice have brain serotonin dysfunction due to a single nucleotide polymorphism (SNP) in tryptophan hydroxylase 2 (TPH2). Brain serotonin dysfunction plays a critical role in depression and anxiety and BALB/c mice exhibit depression- and anxiety-related behaviors. Since depression is common and associated with poor prognosis in HF patients, we examined therapeutic effects of anti-depression drug paroxetine and anti-anxiety drug buspirone that could improve the brain serotonin function in mice. Both drugs reduced cardiac enlargement and improved systolic dysfunction and symptoms of severe congestive HF in DCM mice on the BALB/c background. These results strongly suggest that genetic backgrounds involving brain serotonin dysfunction, such as TPH2 gene SNP, may play an important role in the development of congestive HF in DCM.
authors.affiliation: Department of Clinical Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Sachio
authors.initials: S
authors.lastname: Morimoto
authors.forename: Sachiko
authors.initials: S
authors.lastname: Take
authors.forename: Dong-Yun
authors.initials: DY
authors.lastname: Zhan
authors.forename: Cheng-Kun
authors.initials: CK
authors.lastname: Du
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Wang
authors.forename: Xue-Li
authors.initials: XL
authors.lastname: Fan
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yoshihara
authors.forename: Fumi
authors.initials: F
authors.lastname: Takahashi-Yanaga
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Katafuchi
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sasaguri
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D006321:Heart / Q000187:drug effects; D006333:Heart Failure / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D012701:Serotonin / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology
chemical_list: D058825:Serotonin 5-HT1 Receptor Agonists; D012701:Serotonin