Non-neuronal cholinergic machinery present in cardiomyocytes offsets hypertrophic signals.
Non-neuronal cholinergic machinery present in cardiomyocytes offsets hypertrophic signals.
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DOI：
10.1016/j.yjmcc.2012.05.003
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发表时间：
2012-08
影响因子：
5
通讯作者：
Guatimosim S
中科院分区：
文献类型：
--
作者：
Rocha-Resende C;Roy A;Resende R;Ladeira MS;Lara A;de Morais Gomes ER;Prado VF;Gros R;Guatimosim C;Prado MA;Guatimosim S
最近的研究提供了令人信服的证据，表明增加乙酰胆碱(ACh)水平可以在心力衰竭时起到保护作用，而ACh分泌水平的降低会导致心脏功能障碍。此前的数据显示，心肌细胞本身可以主动分泌ACh，这引发了这样一个问题：这种心肌细胞衍生的ACh是否可能有助于ACh对心脏的保护作用。为了解决这种非神经性ACh机制的功能，我们使用了胆碱酯酶抑制剂和靶向AChE(乙酰胆碱酯酶)的siRNA作为增加心肌细胞分泌ACh的一种方式。通过使用一氧化氮(NO)的形成作为释放ACh的生物传感器，我们发现胆碱酯酶抑制增加了新鲜分离的心室肌细胞中NO的水平，这种作用可被M受体拮抗剂阿托品和抑制ACh的合成或囊泡储存所阻止。在功能上，胆碱酯酶抑制可阻止肾上腺素能过度刺激引起的心肌细胞肥大效应、分子变化和钙瞬变。此外，抑制ACh储存或阿托品可减弱胆碱酯酶抑制的抗肥厚作用。总之，我们的结果表明，心肌细胞具有功能性胆碱能机制，可以抵消高肾上腺素能刺激的有害影响。此外，我们还发现肾上腺素能刺激可上调胆碱能成分的表达水平。我们认为，这种心肌细胞胆碱能信号可以放大心脏副交感神经系统的保护作用，并可能对抗或部分中和肥大的肾上腺素能作用。
Recent work has provided compelling evidence that increased levels of acetylcholine (ACh) can be protective in heart failure, whereas reduced levels of ACh secretion can cause heart malfunction. Previous data show that cardiomyocytes themselves can actively secrete ACh, raising the question of whether this cardiomyocyte derived ACh may contribute to the protective effects of ACh in the heart. To address the functionality of this non-neuronal ACh machinery, we used cholinesterase inhibitors and a siRNA targeted to AChE (acetylcholinesterase) as a way to increase the availability of ACh secreted by cardiac cells. By using nitric oxide (NO) formation as a biological sensor for released ACh, we showed that cholinesterase inhibition increased NO levels in freshly isolated ventricular myocytes and that this effect was prevented by atropine, a muscarinic receptor antagonist, and by inhibition of ACh synthesis or vesicular storage. Functionally, cholinesterase inhibition prevented the hypertrophic effect as well as molecular changes and calcium transient alterations induced by adrenergic overstimulation in cardiomyocytes. Moreover, inhibition of ACh storage or atropine blunted the anti-hypertrophic action of cholinesterase inhibition. Altogether, our results show that cardiomyocytes possess functional cholinergic machinery that offsets deleterious effects of hyperadrenergic stimulation. In addition, we show that adrenergic stimulation upregulates expression levels of cholinergic components. We propose that this cardiomyocyte cholinergic signaling could amplify the protective effects of the parasympathetic nervous system in the heart and may counter-act or partially neutralize hypertrophic adrenergic effects.
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影响因子：
11.1
作者：
Huston JM;Tracey KJ
通讯作者：
Tracey KJ
DOI：
10.1152/ajpheart.00170.2010
发表时间：
2010-09-01
影响因子：
4.8
作者：
English, Brett A.;Appalsamy, Martin;Blakely, Randy D.
通讯作者：
Blakely, Randy D.
影响因子：
5
作者：
Katare, Rajesh G.;Ando, Motonori;Sato, Takayuki
通讯作者：
Sato, Takayuki
影响因子：
4
作者：
Aguiar, Carla J.;Andrade, Vanessa L.;Leite, M. Fatima
通讯作者：
Leite, M. Fatima
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.