Background: Lysophosphatidic acid (LPA) is a small glycerophospholipid that acts as a potent extracellular signal in various biological processes and diseases. Our previous work demonstrated that the expression of the LPA receptors LPA₁ and LPA₃ is elevated in the early postnatal heart. However, the role of this stage-specific expression of LPA₁ and LPA₃ in the heart is unknown./nMethods and Results: By using LPA₃ and LPA₁ knockout mice, and neonatal SD rats treated with Ki16425 (LPA₁/LPA₃ inhibitor), we found that the number of proliferating cardiomyocytes, detected by coimmunostaining pH3, Ki67 or BrdU with cardiac troponin T, was significantly decreased in the LPA₃ knockout mice and the Ki16425-treated rats but not in the LPA₁ knockout mice during the first week of postnatal life. Using a myocardial infarction (MI) model, we found that cardiac function and the number of proliferating cardiomyocytes were decreased in the neonatal LPA₃ KO mice and increased in the AAV9-mediated cardiac-specific LPA₃ overexpression mice. By using lineage tracing and AAV9-LPA₃, we further found that LPA₃ overexpression in adult mice enhances cardiac function and heart regeneration as assessed by pH3-, Ki67-, and Aurora B-positive cardiomyocytes and clonal cardiomyocytes after MI. Genome-wide transcriptional profiling and additional mechanistic studies showed that LPA induces cardiomyocyte proliferation through the PI3K/AKT, BMP-Smad1/5, Hippo/YAP and MAPK/ERK pathways in vitro, whereas only ERK was confirmed to be activated by LPA-LPA₃ signaling in vivo./nConclusion: Our study reports that LPA₃-mediated LPA signaling is a crucial factor for cardiomyocyte proliferation in the early postnatal heart. Cardiac-specific LPA₃ overexpression improved cardiac function and promoted cardiac regeneration after myocardial injury induced by MI. This finding suggested that activation of LPA₃ potentially through AAV-mediated gene therapy might be a therapeutic strategy to improve the outcome after MI.

中文翻译：

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LPA3介导的溶血磷脂酸信号促进小鼠出生后心脏再生

背景：溶血磷脂酸（LPA）是一种小的甘油磷脂，在各种生物过程和疾病中均充当有效的细胞外信号。我们以前的工作表明，LPA受体LPA ₁和LPA ₃的表达在产后早期心脏中升高。然而，尚不清楚心脏中LPA ₁和LPA ₃的这一阶段特异性表达的作用。/n方法和结果：通过使用LPA ₃和LPA ₁敲除小鼠以及Ki16425（LPA ₁ / LPA）治疗的新生SD大鼠₃抑制剂），我们发现在LPA ₃基因敲除小鼠和Ki16425处理的大鼠中，通过将pH3，Ki67或BrdU与心肌肌钙蛋白T共免疫来检测到的增殖性心肌细胞数量显着减少，而在LPA ₁基因敲除小鼠中则没有。产后第一周。使用心肌梗塞（MI）模型，我们发现新生LPA ₃ KO小鼠的心脏功能和增殖性心肌细胞数量减少，而AAV9介导的心脏特异性LPA ₃过表达小鼠的心脏功能和增殖心肌细胞数量增加。通过使用谱系跟踪和AAV9-LPA ₃，我们进一步发现LPA ₃MI后，通过pH3-，Ki67-和Aurora B阳性心肌细胞和克隆型心肌细胞评估，成年小鼠的过度表达可增强心脏功能和心脏再生。基因组范围的转录谱和额外的机理研究表明，通过PI3K / AKT，BMP-的Smad1 / 5 LPA诱导心肌细胞增殖，河马/ YAP和MAPK / ERK途径在体外，而只有ERK确认到由LPA-LPA被激活₃体内信号传导./n结论：我们的研究报告说，LPA ₃介导的LPA信号传导是出生后早期心脏中心肌细胞增殖的关键因素。心脏专用LPA ₃过表达改善心肌梗死后心肌功能，并促进心脏再生。这一发现表明，潜在地通过AAV介导的基因治疗激活LPA ₃可能是改善MI后预后的治疗策略。