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Theranostics 2020; 10(24):10892-10907. doi:10.7150/thno.47913 This issue Cite

Research Paper

LPA₃-mediated lysophosphatidic acid signaling promotes postnatal heart regeneration in mice

Fang Wang^1#, Si Liu^1,2#, Jianqiu Pei^1#, Lin Cai¹, Ning Liu⁴, Tian Liang⁴, Xiaoxuan Dong⁴, Xiangfeng Cong¹, Jerold Chun³, Jinghai Chen^4✉, Shengshou Hu^1✉, Xi Chen^1✉

1. State Key Laboratory of Cardiovascular Disease, Center of Laboratory Medicine, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.
2. Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, 100050, China.
3. Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, United States.
4. Department of Cardiology, The Second Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, 310029 Hangzhou, China.
#These authors contributed equally to this work.

✉ Corresponding authors: Xi Chen, State Key Laboratory of Cardiovascular Disease, Center of Laboratory Medicine, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China. Phone: +86 10 88398584; Fax: +86 10 88396050; E-mail: chenxifwedu.cn; Shengshou Hu, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China. Phone: +86 10 88396011; Fax: +86 10 88396011; E-mail: hussorg; Jinghai Chen, Department of Cardiology, The Second Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, 310029 Hangzhou, China. Phone: +86-571-86971930; E-mail: jinghaichenedu.cn. More

Abstract

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.

Methods 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.

Conclusion: 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.

Keywords: Lysophosphatidic acid, LPA receptor, cardiomyocyte, proliferation, heart regeneration

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