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

在这项研究中，我们探索了脑5-羟色胺功能在充血性心力衰竭(HF)发生中的作用，使用了在不同遗传背景下携带导致扩张型心肌病(DCM)的肌节蛋白突变的敲入小鼠；BALB/c和C57BL/6。背景小鼠，由于色氨酸羟基酶2的单核苷酸多态性而导致脑5-羟色胺功能障碍，在死前发生充血性心力衰竭。相比之下，大脑5-羟色胺功能正常的C57BL/6背景鼠没有出现明显的心力衰竭症状，并突然死亡。脑5-羟色胺功能障碍在抑郁和焦虑中起关键作用，BALB/c小鼠表现出与抑郁和焦虑相关的行为。在BALB/c背景下，可以改善大脑5-羟色胺功能的药物改善了DCM小鼠严重充血性心力衰竭的症状。这些结果有力地表明，先天性或获得性脑5-羟色胺功能障碍可能在DCM充血性心力衰竭的发生中起重要作用。

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.