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

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 LPA 1 and LPA 3 is elevated in the early postnatal heart. However, the role of this stage-specific expression of LPA 1 and LPA 3 in the heart is unknown. Methods and Results: By using LPA 3 and LPA 1 knockout mice, and neonatal SD rats treated with Ki16425 (LPA 1 /LPA 3 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 LPA 3 knockout mice and the Ki16425-treated rats but not in the LPA 1 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 LPA 3 KO mice and increased in the AAV9-mediated cardiac-specific LPA 3 overexpression mice. By using lineage tracing and AAV9-LPA 3 , we further found that LPA 3 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-LPA 3 signaling in vivo . Conclusion: Our study reports that LPA 3 -mediated LPA signaling is a crucial factor for cardiomyocyte proliferation in the early postnatal heart. Cardiac-specific LPA 3 overexpression improved cardiac function and promoted cardiac regeneration after myocardial injury induced by MI. This finding suggested that activation of LPA 3 potentially through AAV-mediated gene therapy might be a therapeutic strategy to improve the outcome after MI.

Metabolomic and transcriptomic studies of improvements in myocardial infarction due to Pycr1 deletion

“… 24 , 25 , 26 , 27 , 28 , 29 Studies have shown that myocardial‐specific overexpression of the small glycerol phospholipid hemolytic phosphatidic acid (LPA) can improve myocardial function and promote heart regeneration after MI. 30 We also observed that LPA was elevated after Pycr1 KO, which may also be one of the ways in which loss of Pycr1 exerts a protective effect. In addition, we observed elevated levels of bile acids in Pycr1 KO mice.…”

Lysophosphatidic Acid Receptor 3 Suppress Neutrophil Extracellular Traps Production and Thrombosis During Sepsis

“…LPA can exert a wide range of biological effects by binding to the LPA receptors (LPA 1-6 ) and signal through numerous effector pathways activated by heterotrimeric G proteins, including G i/o , G 12/13 , G q , and G s ( 44 ). Disturbances in normal LPA signaling may contribute to a range of diseases, including neuropsychiatric disorders, asthma, acute lung injury, fibrosis, and cardiovascular disease ( 36 – 38 , 45 – 47 ). LPA 3 couples to G αi/o and G αq/11 and mediates LPA-induced Ca 2+ mobilization, inhibition and activation of adenylate cyclase, activation of PLC, and activation of MAPK ( 48 ).…”

“…Lysophosphatidic acid (LPA) is a bioactive lipid mediator of inflammation via lysophosphatidic acid receptors 1–6 (LPA 1 –LPA 6 ), contributing to the pathogenesis of many diseases including asthma, acute lung injury, fibrosis, and postnatal heart regeneration ( 36 – 38 ). A study reported LPA 1 knockout reduces LPS-induced inflammatory cytokine signaling in the lungs ( 39 ), and inflammatory cytokines are effective inducers of NETs.…”

Regeneration and proliferation of cardiomyocytes and its microRNA regulatory mechanisms

“…The stroma signals to CMs thus playing a crucial role in their proliferation. Lysophosphatidic acid (LPA) acts as a potent extracellular signal in various biological processes and diseases and LPA3-mediated LPA signaling was shown to play a pivotal role in CMs proliferation (Wang et al, 2020a). The component of extracellular matrix was shown to affect the growth and differentiation of CMs in mice, mediated by agrin (Bassat et al, 2017) and myeloid-derived growth factor (Wang et al, 2020b).…”