Lysophosphatidic acid exerts protective effects on HEI-OC1 cells against cytotoxicity of cisplatin by decreasing apoptosis, excessive autophagy, and accumulation of ROS

Lysophosphatidic acid (LPA) is an active phospholipid signaling molecule that binds to six specific G protein-coupled receptors (LPA(1-6)) on the cell surface and exerts a variety of biological functions, including cell migration and proliferation, morphological changes, and anti-apoptosis. The earliest study from our group demonstrated that LPA treatment could restore cochlear F-actin depolymerization induced by noise exposure, reduce hair cell death, and thus protect hearing. However, whether LPA could protect against cisplatin-induced ototoxicity and which receptors play the major role remain unclear. To this end, we integrated the HEI-OC1 mouse cochlear hair cell line and zebrafish model, and found that cisplatin exposure induced a large amount of reactive oxygen species accumulation in HEI-OC1 cells, accompanied by mitochondrial damage, leading to apoptosis and autophagy. LPA treatment significantly attenuated autophagy and apoptosis in HEI-OC1 cells after cisplatin exposure. Further investigation revealed that all LPA receptors except LPA(3) were expressed in HEI-OC1 cells, and the mRNA expression level of LPA(1) receptor was significantly higher than that of other receptors. When LPA(1) receptor was silenced, the protective effect of LPA was reduced and the proportion of apoptosis cells was increased, indicating that LPA-LPA(1) plays an important role in protecting HEI-OC1 cells from cisplatin-induced apoptosis. In addition, the behavioral trajectory and in vivo fluorescence imaging results showed that cisplatin exposure caused zebrafish to move more actively, and the movement speed and distance were higher than those of the control and LPA groups, while LPA treatment reduced the movement behavior. Cisplatin caused hair cell death and loss in zebrafish lateral line, and LPA treatment significantly protected against hair cell death and loss. LPA has a protective effect on hair cells in vitro and in vivo against the cytotoxicity of cisplatin, and its mechanism may be related to reducing apoptosis, excessive autophagy and ROS accumulation. [Image: see text]