Prostaglandin E1 attenuates AngII-induced cardiac hypertrophy via EP3 receptor activation and Netrin-1upregulation
Prostaglandin E1 attenuates AngII-induced cardiac hypertrophy via EP3 receptor activation and Netrin-1upregulation
复制标题
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
DOI：
10.1016/j.yjmcc.2021.06.009
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发表时间：
2021-06-23
影响因子：
5
通讯作者：
Shen, Linghong
中科院分区：
文献类型：
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作者：
Shen, Yejiao;Wang, Xia;Shen, Linghong
目的：由肾素-血管紧张素-醛固酮系统（RAAS）激活引起的病理性心肌肥厚是心力衰竭的主要原因之一。然而，在目前的临床实践中，靶向RAAS的策略不足以逆转肥大。在这里，我们研究了前列腺素E1（PGE 1）对血管紧张素II（AngII）诱导的心肌肥厚的作用及其潜在的分子机制。方法和结果：成年雄性C57小鼠连续输注AngII或生理盐水，每天用PGE 1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，前列腺素E1改善血管紧张素II诱导的心肌肥大在体内和体外。RNA测序（RNA-seq）和表达模式分析结果表明，Netrin-1（Ntn 1）是PGE 1的特异性靶基因。PGE 1的保护作用在Ntn 1敲低后被消除。此外，京都基因和基因组百科全书（KEGG）分析表明，PGE 1介导的信号通路的变化与丝裂原活化蛋白激酶（MAPK）通路相关。PGE 1抑制Ang II诱导的MAPK信号通路的激活，这种作用被Ntn 1敲低减弱。阻断MAPK信号通路可以挽救Ntn 1基因敲低引起的心肌细胞表型，表明MAPK信号通路可能是Ntn 1的下游效应子。此外，抑制心肌细胞中的E-前列腺素（EP）3受体（与EP 1、EP 2或EP 4受体相反）可逆转PGE 1的作用，而特异性激动剂硫前列酮对EP 3的激活可模拟PGE 1的作用。总结：总之，PGE 1通过激活EP 3受体和上调Ntn 1（其抑制下游MAPK信号通路）来改善AngII诱导的心脏肥大。因此，靶向EP 3以及Ntn 1-MAPK轴可能代表治疗病理性心脏肥大的新方法。
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 AngIIinduced 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.