Stress-Induced Susceptibility to Sudden Cardiac Death in Mice with Altered Serotonin Homeostasis
Stress-Induced Susceptibility to Sudden Cardiac Death in Mice with Altered Serotonin Homeostasis
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DOI：
10.1371/journal.pone.0041184
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发表时间：
2012-07-18
期刊：
影响因子：
3.7
通讯作者：
Sgoifo, Andrea
中科院分区：
文献类型：
--
作者：
Carnevali, Luca;Mastorci, Francesca;Sgoifo, Andrea
在人类中，慢性应激源长期以来一直与心脏病发病率有关。5-羟色胺能神经传递的改变可能是介导应激诱导的心脏功能紊乱的一个重要的病理生理机制。在这里，我们利用5-羟色胺(5-HT1A)受体基因敲除小鼠(KO)，评估了5-羟色胺(5-HT1A)受体在急性和慢性应激条件下心脏功能自主神经调节中的生理作用。当暴露于急性应激源时，KO小鼠表现出比野生型(WTS)小鼠更快的心动过速应激反应和更大程度的心率迷走调制减少。在慢性心理应激期间，22例KO中有6例(27%)死于心脏骤停。接近死亡时，他们表现出严重的心动过缓、心脏间期(P波、PQ和QRS)延长、QRS波群切迹和深度低温。在同一时期，在昼夜节律的光明和黑暗阶段，其余的被敲除的人的心率值都高于WTS。在牺牲时，KO小鼠表现出更多的心肌M受体(M2)的表达，而与WTS相比，它们在心脏大体解剖和心肌纤维化量方面没有差异。这项研究表明，5-HT1A受体的慢性遗传缺失对心血管健康有害，因为它加剧了应激诱导的急性心率上升，并增加了接受慢性应激的小鼠发生心脏性猝死的易感性。
In humans, chronic stressors have long been linked to cardiac morbidity. Altered serotonergic neurotransmission may represent a crucial pathophysiological mechanism mediating stress-induced cardiac disturbances. Here, we evaluated the physiological role of serotonin (5-HT) 1A receptors in the autonomic regulation of cardiac function under acute and chronic stress conditions, using 5-HT1A receptor knockout mice (KOs). When exposed to acute stressors, KO mice displayed a higher tachycardic stress response and a larger reduction of vagal modulation of heart rate than wild type counterparts (WTs). During a protocol of chronic psychosocial stress, 6 out of 22 (27%) KOs died from cardiac arrest. Close to death, they displayed a severe bradycardia, a lengthening of cardiac interval (P wave, PQ and QRS) duration, a notched QRS complex and a profound hypothermia. In the same period, the remaining knockouts exhibited higher values of heart rate than WTs during both light and dark phases of the diurnal rhythm. At sacrifice, KO mice showed a larger expression of cardiac muscarinic receptors (M2), whereas they did not differ for gross cardiac anatomy and the amount of myocardial fibrosis compared to WTs. This study demonstrates that chronic genetic loss of 5-HT1A receptors is detrimental for cardiovascular health, by intensifying acute, stress-induced heart rate rises and increasing the susceptibility to sudden cardiac death in mice undergoing chronic stress.