Aims

Pathological cardiac hypertrophy induced by activation of the renin–angiotensin–aldosterone system (RAAS) is one of the leading causes of heart failure. However, in current clinical practice, the strategy for targeting the RAAS is not sufficient to reverse hypertrophy. Here, we investigated the effect of prostaglandin E1 (PGE1) on angiotensin II (AngII)-induced cardiac hypertrophy and potential molecular mechanisms underlying the effect.

Methods and results

Adult male C57 mice were continuously infused with AngII or saline and treated daily with PGE1 or vehicle for two weeks. Neonatal rat cardiomyocytes were cultured to detect AngII-induced hypertrophic responses. We found that PGE1 ameliorated AngII-induced cardiac hypertrophy both in vivo and in vitro. The RNA sequencing (RNA-seq) and expression pattern analysis results suggest that Netrin-1 (Ntn1) is the specific target gene of PGE1. The protective effect of PGE1 was eliminated after knockdown of Ntn1. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the PGE1-mediated signaling pathway changes are associated with the mitogen-activated protein kinase (MAPK) pathway. PGE1 suppressed AngII-induced activation of the MAPK signaling pathway, and such an effect was attenuated by Ntn1 knockdown. Blockade of MAPK signaling rescued the phenotype of cardiomyocytes caused by Ntn1 knockdown, indicating that MAPK signaling may act as the downstream effector of Ntn1. Furthermore, inhibition of the E-prostanoid (EP) 3 receptor, as opposed to the EP1, EP2, or EP4 receptor, in cardiomyocytes reversed the effect of PGE1, and activation of EP3 by sulprostone, a specific agonist, mimicked the effect of PGE1.

Conclusion

In conclusion, PGE1 ameliorates AngII-induced cardiac hypertrophy through activation of the EP3 receptor and upregulation of Ntn1, which inhibits the downstream MAPK signaling pathway. Thus, targeting EP3, as well as the Ntn1–MAPK axis, may represent a novel approach for treating pathological cardiac hypertrophy.

中文翻译：

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前列腺素 E1 通过 EP3 受体激活和 Netrin-1 上调减轻 AngII 诱导的心脏肥大

目标

肾素-血管紧张素-醛固酮系统（RAAS）激活引起的病理性心脏肥大是心力衰竭的主要原因之一。然而，在目前的临床实践中，针对 RAAS 的策略不足以逆转肥大。在这里，我们研究了前列腺素 E1 (PGE1) 对血管紧张素 II (AngII) 诱导的心脏肥大的影响以及该影响的潜在分子机制。

方法和结果

成年雄性 C57 小鼠连续输注 AngII 或盐水，每天用 PGE1 或载体治疗两周。培养新生大鼠心肌细胞以检测AngII诱导的肥大反应。我们发现 PGE1 在体内和体外都改善了 AngII 诱导的心脏肥大。RNA测序（RNA-seq）和表达模式分析结果表明Netrin-1（Ntn1）是PGE1的特异性靶基因。在敲除 Ntn1 后，PGE1 的保护作用被消除。此外，京都基因和基因组百科全书 (KEGG) 分析表明，PGE1 介导的信号通路变化与丝裂原活化蛋白激酶 (MAPK) 通路有关。PGE1 抑制了 AngII 诱导的 MAPK 信号通路的激活，并且这种作用被 Ntn1 敲低减弱。阻断 MAPK 信号通路挽救了由 Ntn1 敲低引起的心肌细胞表型，表明 MAPK 信号通路可能作为 Ntn1 的下游效应子。此外，与 EP1、EP2 或 EP4 受体相反，抑制心肌细胞中的 E-前列腺素 (EP) 3 受体可逆转 PGE1 的作用，而特定激动剂磺胺前列酮对 EP3 的激活模拟了 PGE1 的作用.

结论

总之，PGE1 通过激活 EP3 受体和上调 Ntn1（抑制下游 MAPK 信号通路）来改善 AngII 诱导的心脏肥大。因此，靶向 EP3 以及 Ntn1-MAPK 轴可能代表一种治疗病理性心脏肥大的新方法。