Geranylgeranyl pyrophosphate synthase facilitates the organization of cardiomyocytes duringmid-gestation through modulating protein geranylgeranylation inmouse heart
Geranylgeranyl pyrophosphate synthase facilitates the organization of cardiomyocytes duringmid-gestation through modulating protein geranylgeranylation inmouse heart
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DOI：
10.1093/cvr/cvy042
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发表时间：
2018-06-01
影响因子：
10.8
通讯作者：
Li, Chaojun
中科院分区：
文献类型：
--
作者：
Chen, Zhong;Xu, Na;Li, Chaojun
目的随着胎盘的发育成熟，心室腔的成熟增强了心脏的收缩能力，以适应胚胎发育的代谢需要。心肌细胞的组织化是心室腔成熟过程中形态重构所必需的。然而，心室腔成熟过程中的心脏细胞结构的建立的机制仍然研究甚少。方法和结果在这里，我们发现，香叶基香叶基焦磷酸合酶（Ggpps），介导的蛋白质香叶基香叶基化，在小鼠心脏的表达增加胎盘功能发病后。通过使用不同的Cre细胞系，我们发现Nkx2.5（Cre/+）细胞系对Ggpps的心脏失活早在E9.5就破坏了蛋白质香叶基香叶基化，这影响了心室腔的成熟并导致妊娠中期胚胎死亡。相反，α-SMA-Cre系介导的蛋白质香叶基香叶基化从E13.5的破坏不影响胚胎心脏发育。对Nkx2.5（Cre/+）; Ggpps（fl/fl）突变体的进一步分析表明，早在E11.5，Ggpps的缺失通过干扰细胞-细胞连接而引起心脏细胞结构紊乱。Ggpps失活降低了Rho GT3香叶基香叶基化及其活性，这可能是细胞-细胞连接破坏的原因。此外，委员会认为，结论GGPPS介导的蛋白质香叶基香叶基化在心室成熟过程中起重要作用，并作为一种阶段特异性信号调节心肌细胞构筑的建立。怀孕
Aims With the maturation of placenta, ventricular chamber maturation enhances cardiac contractile performance to adapt to the metabolic demand of growing embryo. The organization of cardiomyocytes is required for the morphological remodelling in ventricular chamber maturation. However, the mechanism governing the establishment of cardiac cytoarchitecture during ventricular chamber maturation is still poorly studied.Methods and results Here, we found that the expression of geranylgeranyl pyrophosphate synthase (Ggpps), which mediates protein geranylgeranylation, increased in the mouse heart after the onset of placental function. By using different Cre lines, we found that the cardiac inactivation of Ggpps by the Nkx2.5(Cre/+) line disrupted protein geranylgeranylation as early as E9.5, which affected ventricular chamber maturation and resulted in mid-gestational embryonic lethality. In contrast, alpha-SMA-Cre line mediated the disruption of protein geranylgeranylation from E13.5 did not affect embryonic heart development. Further analysis of Nkx2.5(Cre/+); Ggpps(fl/fl) mutants showed that the loss of Ggpps caused disorganized cardiac cytoarchitecture as early as E11.5 by disturbing cell-cell junctions. Ggpps inactivation decreased Rho GTPase geranylgeranylation and their activity, which might account for the disruption of cell-cell junctions. Moreover, elevating the protein geranylgeranylation by supplement of geranylgeranyl pyrophosphate (GGPP) could recover the Ggpps deficient induced defects of cytoarchitecture and cell-cell junctions in vitro and in vivo.Conclusion Our present study demonstrates that GGPPS-mediated protein geranylgeranylation plays an indispensable role in the ventricular chamber maturation and acts as a stage-specific signal to regulate the establishment of cardiac cytoarchitecture during mid-gestation.