Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Physiol Rep. 2021 Oct;9(19):e15060. doi: 10.14814/phy2.15060.
Sphingosine 1-Phosphate receptor 1 (S1P , encoded by S1pr1) is a G protein-coupled receptor that signals in multiple cell types including endothelial cells and cardiomyocytes. Cardiomyocyte-specific deletion of S1pr1 during mouse development leads to ventricular noncompaction, with 44% of mutant mice surviving to adulthood. Adult survivors of embryonic cardiomyocyte S1pr1 deletion showed cardiac hypertrabeculation consistent with ventricular noncompaction. Surprisingly, systolic function in mutant mice was preserved through at least 1 year of age. Cardiac conduction was abnormal in cardiomyocyte S1pr1 mutant mice, with prolonged QRS intervals in mutants as compared with littermate control mice. Immunostaining of hearts from S1pr1 mutant embryos displayed a zone of intermediate Connexin 40 (Cx40) expression in the trabecular myocardium. However, we observed no significant differences in Cx40 and Connexin 43 immunostaining in hearts from adult survivors of embryonic cardiomyocyte S1pr1 deletion, which suggests normalized development of the ventricular conduction system in mutant mice. By contrast, the adult survivors of embryonic cardiomyocyte S1pr1 deletion showed increased cardiac fibrosis as compared with littermate controls. These results demonstrate that ventricular hypertrabeculation caused by embryonic deletion of cardiomyocyte S1pr1 correlates with cardiac fibrosis, which contributes to abnormal ventricular conduction. These results also reveal conduction abnormalities in the setting of hypertrabeculation with normal systolic function, which may be of clinical relevance in humans with ventricular hypertrabeculation.
鞘氨醇 1-磷酸受体 1（S1P，由 S1pr1 编码）是一种 G 蛋白偶联受体，在包括内皮细胞和心肌细胞在内的多种细胞类型中发出信号。在小鼠发育过程中，心肌细胞特异性缺失 S1pr1 会导致心室肌小梁化，44%的突变小鼠存活至成年。胚胎心肌细胞 S1pr1 缺失的成年幸存者表现出与心室肌小梁化一致的心肌肥厚。令人惊讶的是，突变小鼠的收缩功能至少在 1 岁时仍保持正常。心肌细胞 S1pr1 突变小鼠的心脏传导异常，与同窝对照小鼠相比，突变小鼠的 QRS 间隔延长。S1pr1 突变胚胎心脏的免疫染色显示，小梁心肌中有中间 Connexin 40（Cx40）表达区。然而，我们在胚胎心肌细胞 S1pr1 缺失的成年幸存者的心脏中没有观察到 Cx40 和 Connexin 43 免疫染色的显著差异，这表明突变小鼠的心室传导系统发育正常。相比之下，胚胎心肌细胞 S1pr1 缺失的成年幸存者的心脏纤维化程度增加，与同窝对照相比。这些结果表明，胚胎期心肌细胞 S1pr1 缺失引起的心室肌小梁化与心脏纤维化相关，后者导致异常的心室传导。这些结果还揭示了肥厚性心肌中存在传导异常，而收缩功能正常，这在具有心室肌小梁化的人类中可能具有临床相关性。
