LPA-LPA_(3)信号参与调控出生后小鼠的心脏发育

LPA_(3)-mediated Lysophosphatidic Acid Signaling Regulates Heart Development of Postnatal Mice

溶血磷脂酸(lysophosphatidic acid,LPA)是一类结构最简单的生物活性小分子,参与多种细胞的增殖、存活及组织器官的发育。我们前期研究发现,LPA可促进原代大鼠心肌细胞增殖。然而,LPA信号及其受体在心脏发育中的作用仍尚不清晰。为此,首先利用生物信息数据库和实时荧光定量PCR分析了6种LPA受体(LPA1-LPA6)的表达情况,发现LPA_(3)是人和小鼠心脏表达最高的LPA受体,并在小鼠出生后7 d表达到峰值,成年期表达下降。本研究使用LPA_(3)敲除小鼠探究LPA_(3)在出生后小鼠心脏发育中的作用。结果发现,LPA_(3)敲除小鼠出生后1周心肌细胞增殖率显著减少(P<0.05)。心脏超声和病理结果显示,成年LPA_(3)敲除小鼠心脏形态和心功能不受影响(P>0.05),但小鼠心肌细胞代偿性肥大(P<0.05)。此外,对P7 d小鼠给予心梗损伤发现,LPA_(3)敲除小鼠心梗后心功能较对照组显著降低(P<0.05),心肌梗死面积增加(P<0.05)。综上所述,我们的研究表明,LPA_(3)调节的LPA信号参与调节出生后早期心脏发育,提示LPA_(3)可能是治疗心肌损伤的潜在药物靶点。

Lysophosphatidic acid(LPA)is a small bioactive phospholipid that mediates various cellular processes such as proliferation,survival,and migration.In particular,LPA signaling has been shown to affect the development of diverse tissues.Our previous work demonstrated that LPA could promote primary neonatal rat cardiomyocytes proliferation.However,the role of LPA and its receptor in postnatal heart development is unknown.By using databases for biological information and RT-qPCR,we analyzed the expression of six LPA receptors(LPA1-LPA6)and found that LPA_(3) was the most highly expressed LPA receptor in human and mouse hearts.In addition,the expression of LPA_(3) mRNA at P7 peaked at 26-fold higher than adults’expression.Using LPA_(3)-knockout mice,we found that the number of proliferating cardiomyocytes,detected by co-immunostaining pH3 with cardiac troponin T,was significantly decreased in the LPA_(3)-knockout mice during the first week of postnatal life(P<0.05).Furthermore,by using cardiac echocardiography and pathological staining,we found that LPA_(3)-knockout adult mice displayed normal cardiac morphology and function.However,the cardiomyocytes volume increased compensatorily(P<0.05).In addition,using a myocardial infarction(MI)model,we found that the cardiac function decreased and the infracted area increased after myocardial infarction at P7(P<0.05).In summary,our study reported that LPA_(3)-mediated LPA signaling was a crucial factor for heart development in the postnatal heart,which suggested that LPA_(3) might be a potential drug target for the treatment of the myocardial injury.