Direct inhibition of type 5 adenylyl cyclase prevents myocardial apoptosis without functional deterioration
Direct inhibition of type 5 adenylyl cyclase prevents myocardial apoptosis without functional deterioration
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DOI：
10.1074/jbc.m314238200
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发表时间：
2004-09-24
影响因子：
4.8
通讯作者：
Ishikawa, Y
中科院分区：
文献类型：
--
作者：
Iwatsubo, K;Minamisawa, S;Ishikawa, Y
腺苷酸环化酶是β-肾上腺素能受体信号的主要靶酶，当酶催化活性高时，其被P-位点抑制剂（该酶的经典抑制剂）有效且直接地抑制。与β-肾上腺素能受体拮抗剂不同，这是一种对ATP的非竞争性或非竞争性抑制。我们已经研究了我们是否可以利用这种酶的特性来调节β-肾上腺素能受体刺激的差异。在筛选了多种新的和经典的化合物后，我们发现一些化合物，包括1 R，4 R-3-（6-氨基嘌呤-9-基）-环戊烷羧酸羟基酰胺，有效地抑制5型腺苷酸环化酶，主要的心脏亚型，但不抑制其他亚型。在正常小鼠心肌细胞中，低β-肾上腺素能受体刺激引起的收缩抑制效果较差，但5型腺苷酸环化酶抑制剂可有效阻止高β-肾上腺素能受体刺激引起的心肌细胞凋亡。与此相反，当5型腺苷酸环化酶基因敲除小鼠的心肌细胞进行检查，β-肾上腺素能刺激不良诱导凋亡。我们的数据表明，在5型腺苷酸环化酶亚型的水平上通过P-位点抑制剂抑制β-肾上腺素能信号传导可能作为一种有效的方法来防止过度β-肾上腺素能刺激诱导的心肌细胞凋亡，而不会对心肌细胞收缩产生有害影响。
Adenylyl cyclase, a major target enzyme of beta-adrenergic receptor signals, is potently and directly inhibited by P-site inhibitors, classic inhibitors of this enzyme, when the enzyme catalytic activity is high. Unlike beta-adrenergic receptor antagonists, this is a non- or uncompetitive inhibition with respect to ATP. We have examined whether we can utilize this enzymatic property to regulate the effects of beta-adrenergic receptor stimulation differentially. After screening multiple new and classic compounds, we found that some compounds, including 1R, 4R-3-(6-aminopurin-9-yl)-cyclopentanecarboxylic acid hydroxyamide, potently inhibited type 5 adenylyl cyclase, the major cardiac isoform, but not other isoforms. In normal mouse cardiac myocytes, contraction induced by low beta-adrenergic receptor stimulation was poorly inhibited with this compound, but the induction of cardiac myocyte apoptosis by high beta-adrenergic receptor stimulation was effectively prevented by type 5 adenylyl cyclase inhibitors. In contrast, when cardiac myocytes from type 5 adenylyl cyclase knock-out mice were examined, beta-adrenergic stimulation poorly induced apoptosis. Our data suggest that the inhibition of beta-adrenergic signaling at the level of the type 5 adenylyl cyclase isoform by P-site inhibitors may serve as an effective method to prevent cardiac myocyte apoptosis induced by excessive beta-adrenergic stimulation without deleterious effect on cardiac myocyte contraction.