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首页> 外文期刊>American Journal of Physiology >Activation of IP prostanoid receptors prevents cardiomyocyte hypertrophy via cAMP-dependent signaling.
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Activation of IP prostanoid receptors prevents cardiomyocyte hypertrophy via cAMP-dependent signaling.

机译：IP前列腺素受体的激活可通过cAMP依赖性信号传导阻止心肌肥大。

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The antihypertrophic action of angiotensin-converting enzyme inhibitors in the heart results partly from local potentiation of bradykinin. We have demonstrated that the antihypertrophic action of bradykinin is mediated by the release of nitric oxide from endothelium and elevation of cardiomyocyte cGMP. Whether other paracrine factors derived from the coronary endothelium, such as prostacyclin (PGI2), may act to prevent hypertrophy has not been explored. In the vasculature, activation by PGI2 of IP and EP1 prostanoid receptors elicits vasodilatation (via cAMP-dependent signaling) and vasoconstriction, respectively. The present objective was to determine whether IP prostanoid receptor activation has antihypertrophic actions in adult rat cardiomyocytes (ARCM). The selective IP agonist cicaprost (1 microM) virtually abolished the increase in [3H]phenylalanine incorporation (a marker of hypertrophy) induced either by endothelin-1 (ET-1; 60 nM, n = 10, P < 0.005) or by angiotensin II (1 microM, n = 6, P < 0.005). Cicaprost also inhibited ET-1 induction of c-fos mRNA expression, an additional marker of hypertrophy in ARCM (n = 5, P < 0.005). In the absence of hypertrophic stimuli, cicaprost alone did not significantly influence either marker. The antihypertrophic actions of cicaprost were mimicked by the dual IP/EP1 agonist iloprost (1 microM) in the presence of the EP1 antagonist AH-6809 (3 microM). Furthermore, cicaprost modestly but significantly increased cardiomyocyte cAMP content by 13 +/- 6% (P < 0.05, n = 4), and the antihypertrophic effect of cicaprost was lost in the presence of the cAMP-dependent protein kinase inhibitor H-89 (1 microM, n = 5, P < 0.05). However, ET-1 also induced increases in the activity of the intracellular growth signals ERK1 (by 3-fold) and ERK2 (by 5-fold) in ARCM, and these were not inhibited by cicaprost (P < 0.01, n = 5). Activation of IP receptors thus represents a novel approach to prevention of hypertrophy, and this effect is linked to cAMP-dependent signaling.
机译：血管紧张素转换酶抑制剂在心脏中的抗肥大作用部分归因于缓激肽的局部增强。我们已经证明缓激肽的抗肥大作用是由内皮中一氧化氮的释放和心肌细胞cGMP的升高介导的。尚未探讨其他源自冠状动脉内皮的旁分泌因子，例如前列环素（PGI2）是否可起到预防肥大的作用。在脉管系统中，IP和EP1前列腺素受体的PGI2激活分别引起血管舒张（通过cAMP依赖性信号传导）和血管收缩。本目标是确定IP前列腺素受体激活在成年大鼠心肌细胞（ARCM）中是否具有抗肥大作用。选择性IP激动剂cicaprost（1 microM）实际上消除了由内皮素1（ET-1; 60 nM，n = 10，P <0.005）或血管紧张素引起的[3H]苯丙氨酸掺入（肥大的标志）的增加II（1 microM，n = 6，P <0.005）。 Cicaprost还抑制ET-1诱导c-fos mRNA表达，这是ARCM肥大的另一个标志（n = 5，P <0.005）。在缺乏肥厚刺激的情况下，单独使用西卡前列素不会显着影响任何一种标记物。在EP1拮抗剂AH-6809（3 microM）存在的情况下，双重IP / EP1激动剂伊洛前列素（1 microM）模拟了cicaprost的抗肥大作用。此外，西卡前列素适度但明显增加了心肌cAMP含量13 +/- 6％（P <0.05，n = 4），并且在存在cAMP依赖性蛋白激酶抑制剂H-89的情况下失去了西卡前列素的抗肥大作用（ 1 microM，n = 5，P <0.05）。然而，ET-1还诱导了ARCM中细胞内生长信号ERK1（增加3倍）和ERK2（增加5倍）的活性，而西卡前列素未对其抑制（P <0.01，n = 5）。 。因此，IP受体的激活代表了一种预防肥大的新方法，并且这种作用与cAMP依赖性信号传导有关。

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