Pathogenic mechanism of congestive heart failure in a mouse model of dilated cardiomyopathy with brain serotonin dysfunction

在这项研究中，我们探讨了脑5-羟色胺功能在充血性心力衰竭（HF）的发展中的作用，使用基因敲入小鼠携带肌节蛋白突变，导致扩张型心肌病（DCM）在不同的遗传背景; BALB/c和C57 B1/6。由于色氨酸羟化酶2中的单核苷酸多态性而具有脑5-羟色胺功能障碍的BALB/c背景小鼠在死亡前发展为充血性HF。相反，具有正常脑5-羟色胺功能的C57 B1/6背景小鼠没有明显的HF症状并突然死亡。脑5-羟色胺功能障碍在抑郁和焦虑中起着关键作用，BALB/c小鼠表现出抑郁和焦虑相关的行为。改善脑5-羟色胺功能的药物改善了BALB/c背景下DCM小鼠严重充血性HF的症状。这些结果强烈提示先天性或获得性脑5-羟色胺功能障碍可能在扩张型心肌病充血性心力衰竭的发展中起重要作用。

In this study, we explored the role of brain serotonin function in the development of congestive heart failure (HF), using knock-in mice bearing a sarcomeric protein mutation that causes dilated cardiomyopathy (DCM) on different genetic backgrounds; BALB/c and C57Bl/6. BALB/c background mice, which have brain serotonin dysfunction due to a single nucleotide polymorphism in tryptophan hydroxylase 2, developed congestive HF before died. In contrast, C57Bl/6 background mice with normal brain serotonin function developed no overt HF symptoms and died suddenly. Brain serotonin dysfunction plays a critical role in depression and anxiety and BALB/c mice exhibit depression- and anxiety-related behaviors. Drugs that could improve the brain serotonin function improved symptoms of severe congestive HF in DCM mice on the BALB/c background. These results strongly suggest that congenital or acquired brain serotonin dysfunction may play an important role in the development of congestive HF in DCM.