The alpha-1D Is the predominant alpha-1-adrenergic receptor subtype in human epicardial coronary arteries.
The alpha-1D Is the predominant alpha-1-adrenergic receptor subtype in human epicardial coronary arteries.
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DOI：
10.1016/j.jacc.2009.05.056
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发表时间：
2009-09-22
影响因子：
24
通讯作者：
Simpson, Paul C.
中科院分区：
文献类型：
--
作者：
Jensen, Brian C.;Swigart, Philip M.;Laden, Marie-Eve;DeMarco, Teresa;Hoopes, Charles;Simpson, Paul C.
目的是鉴定人类冠状动脉中的α -1-肾上腺素能受体（α1-AR）亚型。α1- ar调节人冠状动脉血流量。α1-ARs以α1A、α1B和α1D三种分子亚型存在，α1D亚型介导小鼠冠状动脉血管收缩。然而，α1A被认为是人类冠状动脉中唯一的亚型。我们从19名移植受者和6名未使用的供者（年龄19 - 70岁，68%为男性，32%患有冠状动脉疾病）获得人心外膜冠状动脉和左心室（LV）心肌。培养冠状动脉环和人冠状动脉平滑肌细胞。采用实时定量反转录PCR检测α1-和β-AR亚型mrna；和亚型蛋白，通过放射性配体结合和ERK激活。α1D亚型占冠状动脉α1-AR mRNA总量的85%，α1-AR蛋白总量的75%，α1D刺激可激活ERK。而左室心肌α1D较低。冠状动脉α - 1- ar总水平为β- ar的三分之一，占β2亚型的99%。α1D亚型在人类心外膜冠状动脉中占主导地位并具有功能，而α1A和α1B的水平非常低。这种分布与小鼠相似，心肌α1A和α 1b - ar介导有益的功能反应，冠状动脉α 1d介导血管收缩。因此，α 1d选择性拮抗剂可能介导冠状动脉血管舒张，而目前使用的非选择性α1-AR拮抗剂对心脏没有负面影响。此外，有可能选择性地激活有益的心肌α1A和/或α1B-AR信号而不引起冠状动脉收缩。
The goal was to identify alpha-1-adrenergic receptor (α1-AR) subtypes in human coronary arteries. The α1-ARs regulate human coronary blood flow. α1-ARs exist as three molecular subtypes, α1A, α1B, and α1D, and the α1D subtype mediates coronary vasoconstriction in the mouse. However, the α1A is thought to be the only subtype in human coronary arteries. We obtained human epicardial coronary arteries and left ventricular (LV) myocardium from 19 transplant recipients and 6 unused donors (age 19–70 years; 68% male; 32% with coronary artery disease). We cultured coronary rings and human coronary smooth muscle cells. We assayed α1- and β-AR subtype mRNAs by quantitative real-time reverse transcription PCR; and subtype proteins, by radioligand binding and ERK activation. The α1D subtype was 85% of total coronary α1-AR mRNA and 75% of total α1-AR protein, and α1D stimulation activated ERK. In contrast, the α1D was low in LV myocardium. Total coronary α1-AR levels were one-third of β-ARs, which were 99% the β2 subtype. The α1D subtype is predominant and functional in human epicardial coronary arteries, whereas the α1A and α1B are present at very low levels. This distribution is similar to the mouse, where myocardial α1A and α1B-ARs mediate beneficial functional responses, and coronary α1Ds mediate vasoconstriction. Thus, α1D-selective antagonists might mediate coronary vasodilation, without the negative cardiac effects of non-selective α1-AR antagonists in current use. Furthermore, it could be possible to selectively activate beneficial myocardial α1A and/or α1B-AR signaling without causing coronary vasoconstriction.
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