Inhibition of phenylephrine-induced cardiomyocyte hypertrophy by activation of multiple adenosine receptor subtypes
Inhibition of phenylephrine-induced cardiomyocyte hypertrophy by activation of multiple adenosine receptor subtypes
复制标题
DOI：
10.1124/jpet.104.073122
复制
发表时间：
2005-01-01
影响因子：
3.5
通讯作者：
Karmazyn, M
中科院分区：
文献类型：
--
作者：
Gan, XHT;Rajapurohitam, V;Karmazyn, M
血浆腺苷水平在包括高血压和心力衰竭的心血管疾病中升高，并且已经提出核苷作为内源性抗心肌重塑因子。我们研究了腺苷受体激活对离体培养的新生大鼠心室肌细胞苯肾上腺素诱导的肥大的调节作用。苯丙氨酸（10 μ M）使细胞大小增加35%，并显著增加心房利钠肽的表达。这些作用被稳定的腺苷类似物2-氯腺苷降低，并被腺苷A1受体激动剂N-6-环戊基腺苷（1 μ M）、A（2A）受体激动剂2-对-（2-羧乙基）苯乙基氨基-5 '-N-乙基羧酰胺腺苷（100 nM）和A（3）受体激动剂N-6-（3-碘苄基）腺苷-5'-甲基脲酰胺（100 nM）完全阻断。所有三种激动剂的抗肥大作用被其各自的拮抗剂完全逆转。苯异黄酮显著上调即刻早期基因c-fos的表达，尤其是在苯异黄酮处理的前30分钟内。所有腺苷受体激动剂几乎完全抑制这些作用。虽然苯肾上腺素也诱导p38丝裂原活化蛋白激酶和细胞外信号调节激酶的早期刺激，这些反应不受腺苷激动剂。G-蛋白调节因子RGS 2和RGS 4的表达增加了近3倍，苯丙氨酸治疗，虽然这是完全防止腺苷受体激动剂。这些药物还阻断苯肾上腺素上调肥大肌细胞中Na/H交换亚型1（NHE 1）表达的能力。因此，我们的研究结果表明，腺苷的抗肥大作用，通过多种受体亚型，通过一种机制，涉及下调NHE 1的表达。阻止G蛋白信号传导（RGS）上调的调节剂的能力进一步表明腺苷受体活化使导致肥大反应的信号传导最小化。
Plasma adenosine levels are elevated in cardiovascular disease including hypertension and heart failure, and the nucleoside has been proposed to serve as an endogenous antimyocardial remodeling factor. We studied the modulation of phenylephrine-induced hypertrophy by adenosine receptor activation in isolated neonatal cultured ventricular myocytes. Phenylephrine (10 muM) increased cell size by 35% and significantly increased expression of atrial natriuretic peptide. These effects were reduced by the stable adenosine analog 2-chloroadenosine and were completely blocked by the adenosine A 1 receptor agonist N-6-cyclopentyladenosine (1 muM), the A(2A) receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (100 nM), and the A(3) receptor agonist N-6-(3-iodobenzyl) adenosine-5'-methyluronamide (100 nM). The antihypertrophic effects of all three agonists were completely reversed by their respective antagonists. Phenylephrine significantly up-regulated expression of the immediate early gene c-fos especially within the first 30 min of phenylephrine treatment. These effects were almost completely inhibited by all adenosine receptor agonists. Although phenylephrine also induced early stimulation of both p38 mitogen-activated protein kinase and extracellular signal-regulated kinase, these responses were unaffected by adenosine agonists. The expression of the G-protein regulatory factors RGS2 and RGS4 were increased by nearly 3-fold by phenylephrine treatment although this was completely prevented by adenosine receptor agonists. These agents also blocked the ability of phenylephrine to up-regulate Na/H exchange isoform 1 (NHE1) expression in hypertrophied myocytes. Thus, our results demonstrate an antihypertrophic effect of adenosine acting via multiple receptor subtypes through a mechanism involving down-regulation of NHE1 expression. The ability to prevent regulators of G-protein signaling (RGS) up-regulation further suggests that adenosine receptor activation minimizes signaling which leads to hypertrophic responses.