Role of brain serotonin dysfunction in the pathophysiology of congestive heart failure
Role of brain serotonin dysfunction in the pathophysiology of congestive heart failure
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脑血清素功能障碍在充血性心力衰竭病理生理学中的作用
DOI：
10.1016/j.yjmcc.2012.08.006
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发表时间：
2012
影响因子：
5
通讯作者：
Sasaguri T
中科院分区：
文献类型：
--
作者：
Li L;Morimoto S;Take S;Zhan D.-Y;Du C.-K;Wang Y.-Y;Fan X.-L;Yoshihara T;Takahashi-Yanaga F;Katafuchi T;Sasaguri T
遗传性或非遗传性扩张型心肌病（DCM）患者在发生充血性心力衰竭（HF）或伴有轻微或无明显HF症状的猝死后出现多种疾病表型导致死亡，表明环境和/或遗传因素可能改变DCM的疾病表型。在本研究中，我们试图探索影响单基因遗传性人类DCM疾病表型的未知遗传因素。携带导致DCM的肌肉蛋白突变的敲入小鼠在不同的遗传背景下被创造出来；BALB/c和C57Bl/6。BALB/c背景下的DCM小鼠在死亡前表现为心脏增大和收缩功能障碍，并发充血性心力衰竭。相比之下，C57Bl/6背景的DCM小鼠没有出现明显的HF症状并突然死亡，尽管它们表现出相当大的心脏增大和收缩功能障碍。由于色氨酸羟化酶2 （TPH2）的单核苷酸多态性（SNP）， BALB/c小鼠存在脑血清素功能障碍。脑血清素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。由于心衰患者抑郁很常见，且与预后不良有关，我们检测了抗抑郁药物帕罗西汀和抗焦虑药物丁螺环酮的治疗效果，它们可以改善小鼠脑血清素功能。两种药物均可减少BALB/c背景下DCM小鼠的心脏增大，改善收缩功能障碍和严重充血性HF症状。这些结果强烈提示，涉及脑5 -羟色胺功能障碍的遗传背景，如TPH2基因SNP，可能在DCM患者充血性HF的发展中起重要作用。
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.