Cholinergic signaling exerts protective effects in models of sympathetic hyperactivity-induced cardiac dysfunction.
Cholinergic signaling exerts protective effects in models of sympathetic hyperactivity-induced cardiac dysfunction.
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DOI：
10.1371/journal.pone.0100179
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Guatimosim S
中科院分区：
文献类型：
--
作者：
Gavioli M;Lara A;Almeida PW;Lima AM;Damasceno DD;Rocha-Resende C;Ladeira M;Resende RR;Martinelli PM;Melo MB;Brum PC;Fontes MA;Souza Santos RA;Prado MA;Guatimosim S
心脏的胆碱能控制由两个不同的分支发挥作用;自主成分由副交感神经系统代表，最近描述的非神经元心肌细胞胆碱能机制。先前的证据表明，胆碱能功能降低导致对心肌的有害影响。然而，增加胆碱能信号的条件下，是否可以抵消交感神经过度兴奋引起的病理性重塑，其后果，这两个胆碱能轴是未知的。在这里，我们研究了两种交感神经功能亢进模型：i）异丙肾上腺素（ISO）诱发的慢性β-肾上腺素能受体刺激，和ii）缺乏突触前肾上腺素能受体的α2A/α 2C-肾上腺素能受体敲除（KO）小鼠。在这两种模型中，胆碱能信号通过给予胆碱酯酶抑制剂吡啶斯的明而增加。首先，我们观察到异丙肾上腺素产生自主神经失衡，其特征是交感神经张力增加和副交感神经张力减少。在这种情况下，转录胆碱能蛋白在心室肌细胞上调，表明非神经元胆碱能机制被激活肾上腺素能受体。吡斯的明治疗可防止ISO对自主神经功能和心室胆碱能机制的影响，并抑制心脏重塑。与野生型小鼠相比，α2A/α2C-KO小鼠的心室收缩减少，胆碱酯酶抑制剂也可逆转这种功能障碍。因此，在交感神经驱动或ACh可用性增加的条件下，心脏副交感神经系统和非神经元心肌细胞胆碱能机制以相反的方向调节。此外，我们的数据支持的想法，通过恢复乙酰胆碱的可用性吡啶斯的明是有益的心脏病。
Cholinergic control of the heart is exerted by two distinct branches; the autonomic component represented by the parasympathetic nervous system, and the recently described non-neuronal cardiomyocyte cholinergic machinery. Previous evidence has shown that reduced cholinergic function leads to deleterious effects on the myocardium. Yet, whether conditions of increased cholinergic signaling can offset the pathological remodeling induced by sympathetic hyperactivity, and its consequences for these two cholinergic axes are unknown. Here, we investigated two models of sympathetic hyperactivity: i) the chronic beta-adrenergic receptor stimulation evoked by isoproterenol (ISO), and ii) the α2A/α2C-adrenergic receptor knockout (KO) mice that lack pre-synaptic adrenergic receptors. In both models, cholinergic signaling was increased by administration of the cholinesterase inhibitor, pyridostigmine. First, we observed that isoproterenol produces an autonomic imbalance characterized by increased sympathetic and reduced parasympathetic tone. Under this condition transcripts for cholinergic proteins were upregulated in ventricular myocytes, indicating that non-neuronal cholinergic machinery is activated during adrenergic overdrive. Pyridostigmine treatment prevented the effects of ISO on autonomic function and on the ventricular cholinergic machinery, and inhibited cardiac remodeling. α2A/α2C-KO mice presented reduced ventricular contraction when compared to wild-type mice, and this dysfunction was also reversed by cholinesterase inhibition. Thus, the cardiac parasympathetic system and non-neuronal cardiomyocyte cholinergic machinery are modulated in opposite directions under conditions of increased sympathetic drive or ACh availability. Moreover, our data support the idea that pyridostigmine by restoring ACh availability is beneficial in heart disease.
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影响因子：
6.1
作者：
Ferreira, Anderson J.;Oliveira, Thauana L.;Santos, Robson A. S.
通讯作者：
Santos, Robson A. S.
影响因子：
2.5
作者：
de Castro, B. M.;Pereira, G. S.;Prado, M. A. M.
通讯作者：
Prado, M. A. M.
影响因子：
3.3
作者：
De Angelis, K;Wichi, RB;Irigoyen, MC
通讯作者：
Irigoyen, MC
影响因子：
16.2
作者：
Prado, Vania F.;Martins-Silva, Cristina;Prado, Marco A. M.
通讯作者：
Prado, Marco A. M.
影响因子：
5
作者：
Oliveira, EA;Krieger, JE
通讯作者：
Krieger, JE