Semaphorin 3E/PlexinD1 signaling is required for cardiac ventricular compaction
Semaphorin 3E/PlexinD1 signaling is required for cardiac ventricular compaction
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DOI：
10.1172/jci.insight.125908
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发表时间：
2019-08-22
期刊：
影响因子：
8
通讯作者：
Singh, Manvendra K.
中科院分区：
文献类型：
--
作者：
Sandireddy, Reddemma;Cibi, Dasan Mary;Singh, Manvendra K.
左心室致密化不全（LVNC）是遗传性心肌病最常见的形式之一，其特征是胎儿发育期间小梁过度形成和心肌致密化受损。 LVNC 患者发生左/右心室衰竭或两者兼而有之的风险较高。尽管心室发育的关键调节因子已得到充分研究，但信号蛋白 (Sema)/plexin 信号传导在此过程中的作用仍知之甚少。在本文中，我们证明内皮细胞中的 3 类 Sema 受体 Plxnd1 的基因缺失会导致严重的心室缺陷。与 LVNC 患者类似，他们的特点是过度小梁形成和不致密化。 Plxnd1 的缺失会导致细胞外基质蛋白水解基因的表达减少，从而导致心肌胶的过度沉积。我们证明 Plxnd1 缺陷与 Notch1 表达及其下游靶基因的增加有关。此外，Notch 信号通路的抑制部分挽救了 Pixnd1 突变体中存在的过度小梁化和不致密表型。此外，我们证明 Semaphorin 3E (Sema3E) 是 PlexinD1 的已知配体之一，在发育中的心脏中表达，并且是心肌压缩所必需的。总的来说，我们的研究揭示了我们认为之前未描述过的 Sema3E/PlexinD1 信号通路在心肌小梁形成和致密过程中的作用。
Left ventricular noncompaction (LVNC) is one of the most common forms of genetic cardiomyopathy characterized by excessive trabeculation and impaired myocardial compaction during fetal development. Patients with LVNC are at higher risk of developing left/right ventricular failure or both. Although the key regulators for cardiac chamber development are well studied, the role of semaphorin (Sema)/plexin signaling in this process remains poorly understood. In this article, we demonstrate that genetic deletion of Plxnd1, a class-3 Sema receptor in endothelial cells, leads to severe cardiac chamber defects. They were characterized by excessive trabeculation and noncompaction similar to patients with LVNC. Loss of Plxnd1 results in decreased expression of extracellular matrix proteolytic genes, leading to excessive deposition of cardiac jelly. We demonstrate that Plxnd1 deficiency is associated with an increase in Notch1 expression and its downstream target genes. In addition, inhibition of the Notch signaling pathway partially rescues the excessive trabeculation and noncompaction phenotype present in Pixnd1 mutants. Furthermore, we demonstrate that Semaphorin 3E (Sema3E), one of PlexinD1's known ligands, is expressed in the developing heart and is required for myocardial compaction. Collectively, our study uncovers what we believe to be a previously undescribed role of the Sema3E/PlexinD1 signaling pathway in myocardial trabeculation and the compaction process.