Tight control of adrenal medulla catecholamine release by alpha 2C-adrenergic receptors influences susceptibility to heart failure.
Tight control of adrenal medulla catecholamine release by alpha 2C-adrenergic receptors influences susceptibility to heart failure.
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α2C-肾上腺素能受体严格控制肾上腺髓质儿茶酚胺的释放会影响心力衰竭的易感性。
DOI：
10.1016/j.cardiores.2007.07.005
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发表时间：
2007
影响因子：
10.8
通讯作者：
Liggett,StephenB
中科院分区：
文献类型：
--
作者：
Petrashevskaya,Natalia;Liggett,StephenB
心脏病基因组学计划，马里兰州大学，医学院，巴尔的摩，MD，美国肌细胞上表达的β-肾上腺素能受体（βAR）在被儿茶酚胺肾上腺素和去甲肾上腺素激活时起增加心脏收缩力的作用。然而，在慢性心力衰竭中，持续的激动导致心室功能的进行性丧失[1，2]。α 2 AR在心脏突触前神经和肾上腺髓质嗜铬细胞上表达，部分调节儿茶酚胺的释放。在这个问题上，Gilsbach et al. [3]表明α2CAR亚型在心力衰竭背景下肾上腺分泌肾上腺素中发挥关键作用。心脏交感神经的突触前去甲肾上腺素释放受到α 2A-和α2CAR的调节[4，5]。释放的去甲肾上腺素与这些受体的结合以经典的负反馈方式减少随后的释放，提供了调节反应的主要机制。α2AAR似乎对调节高频刺激的去甲肾上腺素释放特别重要，而α2CAR主要调节低频刺激的释放。肾上腺髓质嗜铬细胞释放肾上腺素（以及较小程度的去甲肾上腺素）进入循环也受到这些细胞上表达的α 2CAR的类似调节[6，7]。Gilsbach等人[3]表明在杂合α2CAR敲除小鼠中研究的α 2CAR的正常补体的一半足以引起肾上腺肾上腺素释放的显著增加。此外，这些小鼠在压力超负荷（主动脉缩窄）条件下更容易发生心脏肥大和衰竭。鉴于该表型仅发生α2CAR表达降低50%，表明肾上腺α2CAR受体储备很少或没有。事实上，当研究α2C+/+、α2C+/−和α2C−/−小鼠时，大多数参数遵循线性基因-剂量反应。这表明受体本身（及其功能能力）是调节儿茶酚胺释放的限速成分。潜在地，破坏该途径的任何过程（通过受体、G蛋白、效应物或调节激酶的表达或功能的改变）可能对心力衰竭的风险或进展具有显著影响，并且该“节点”可能特别适合于治疗干预[8]。
Cardiopulmonary Genomics Program, University of Maryland, School of Medicine, Baltimore, MD, United States β-Adrenergic receptors (βAR) expressed on myocytes act to increase cardiac contractility when activated by the catecholamines epinephrine and norepinephrine. In chronic heart failure, though, persistent activation leads to progressive loss of ventricular function [1, 2]. The α2ARs, expressed on cardiac presynaptic nerves and adrenal medulla chromaffin cells, partially regulate catecholamine release. In this issue, Gilsbach et al.[3] show the critical role of the α2CAR subtype in epinephrine secretion from the adrenal gland in the context of heart failure.Presynaptic norepinephrine release from cardiac sympathetic nerves is regulated by both α2A-and α2CAR [4, 5]. Binding of released norepinephrine to these receptors acts to decrease subsequent release in a classic negative feedback fashion, providing a major mechanism for regulation of the response. The α2AAR appears to be particularly important for regulation of high frequency-stimulated norepinephrine release while the α2CAR primarily regulates low frequency-stimulated release. Epinephrine (and, to a lesser extent, norepinephrine) release from adrenal medulla chromaffin cells into the circulation is also under similar regulation by α2CARs expressed on these cells [6, 7]. Gilsbach et al.[3] show that one half of the normal complement of α2CARs, as studied in heterozygous α2CAR knockout mice, is sufficient to cause a substantial increase in adrenal epinephrine release. Also, these mice were more susceptible to development of cardiac hypertrophy and failure under pressure overload (aortic banding) conditions. Given that this phenotype occurred with only a 50% decrease in α2CAR expression implies that there is little or no adrenal α2CAR receptor reserve. Indeed, most parameters followed a linear gene-dose response when α2C+/+, α2C+/−, and α2C−/− mice were studied. This points to the receptor itself (and its functional capacity) as a rate-limiting component in regulating catecholamine release. Potentially, any process that disrupts this pathway (via alterations in expression or function of the receptor, G-protein, effector, or regulating kinases) could have a significant effect on the risk or progression of heart failure, and this “nodal point” may be particularly amenable to therapeutic intervention [8].