JTE-013 mediates RhoA/ROCKl/Drpl signaling axis regulating mitochondrial damage and apoptosis to alleviate allergic rhinitis

Jiao CHEN; Long-Zhu DAI; Mu CHEN; Yi-Lan SONG; Guang-Hai YAN; Chong-Yang WANG; Yong-De JIN; Jiao CHEN; Mu CHEN; Yong-De JIN; Long-Zhu DAI; Yi-Lan SONG; Guang-Hai YAN; Chong-Yang WANG

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JTE-013 mediates RhoA/ROCKl/Drpl signaling axis regulating mitochondrial damage and apoptosis to alleviate allergic rhinitis

Author: Jiao CHEN ¹ ; Long-Zhu DAI ¹ ; Mu CHEN ¹ ; Yi-Lan SONG ¹ ; Guang-Hai YAN ¹ ; Chong-Yang WANG ¹ ; Yong-De JIN ¹ ; Jiao CHEN ² ; Mu CHEN ² ; Yong-De JIN ² ; Long-Zhu DAI ³ ; Yi-Lan SONG ³ ; Guang-Hai YAN ³ ; Chong-Yang WANG ³
Author Information

1. Jilin Key Laboratory of Immune and Targeted Research on Common Allergic Diseases, School of Medicine
2. Dept of Otorhinolaryngology, Affiliated Hospital of Yanbian University, School of Medicine
3. Dept of Anatomy, Yanbian University, School of Medicine
Publication Type:Journal Article
Keywords: allergic rhinitis; Apoptosis; DRP1; JTE-013; mitochondrial injury; RhoA/Rho-associated protein kinase pathway
From: Chinese Pharmacological Bulletin 2023;39(9):1638-1647
CountryChina
Language:Chinese
Abstract: Aim To investigate the protective effect and mechanism of JTE-013 on allergic rhinitis (AR) by regulating mitochondrial injury and apoptosis through RhoA/ROCKl/Drpl pathway. Methods AR model was established by ovalbumin (OVA) in mice. Nasal tissue sections were then stained with HE, TUNEL and DHE. Western blot assay. In vitro, human nasal epithelial cells (HNEpCs) were stimulated with human recombinant interleukin-13 (IL-13), and the effects of JTE-013 and Y27632-related protein expression were detected by Western blot. Immunofluorescence was used to observe the effects of JTE-013 and Y 27632 on total ROS, mitochondrial membrane potential and mitochondrial ROS generation, Drpl translocation and Cyt-c expression in cells. Results JTE-013 reduced the frequency of nose rubbing and sneezing, reduced nasal mucosal thickening and decreased eosinophil infiltration in AR mice. TUNEL and DHE staining results suggested that JTE-013 could inhibit apoptosis and reduce ROS expression in mouse nasal epithelial cells. Western blot showed that both JTE-013 and Y 27632 could significantly reduce RhoA, ROCK1, Drpl and p-Drpl(616), inhibit the expression of apoptotic proteins Bax, cleaved-caspase-3, Cyt-c, cleavedcaspase-9 and up-regulate the expression of p-Drpl (637) and Bcl-2. Immunofluorescence showed that inhibitors of JTE-013 or ROCK1 almost blocked IL-13mediated increase in ROS and mtROS production, inhibited decrease in mitochondrial membrane potential, and blocked Cyt-c expression and Drpl translocation in nasal mucosal epithelial cells. Conclusion JTE-013 can regulate the morphology and function of mitochondria by inhibiting RhoA/ROCKl/Drpl signaling axis, thereby alleviating nasal epithelial cell inflammation in mice with allergic rhinitis.