Pulmonary hypertension (PH) is a life-threatening cardiopulmonary disease characterized by pulmonary vascular remodeling. Excessive growth and migration of pulmonary artery smooth muscle cells (PASMCs) are believed to be major contributors to pulmonary vascular remodeling. Ubiquitin-specific protease 15 (USP15) is a vital deubiquitinase that has been shown to be critically involved in many pathologies. However, the effect of USP15 on PH has not yet been explored. In this study, the upregulation of USP15 was identified in the lungs of PH patients, mice with SU5416/hypoxia (SuHx)-induced PH and rats with monocrotaline (MCT)-induced PH. Moreover, adeno-associated virus-mediated functional loss of USP15 markedly alleviated PH exacerbation in SuHx-induced mice and MCT-induced rats. In addition, the abnormal upregulation and nuclear translocation of YAP1/TAZ was validated after PH modeling. Human pulmonary artery smooth muscle cells (hPASMCs) were exposed to hypoxia to mimic PH in vitro, and USP15 knockdown significantly inhibited cell proliferation, migration, and YAP1/TAZ signaling in hypoxic hPASMCs. Rescue assays further suggested that USP15 promoted hPASMC proliferation and migration in a YAP1/TAZ-dependent manner. Coimmunoprecipitation assays indicated that USP15 could interact with YAP1, while TAZ bound to USP15 after hypoxia treatment. We further determined that USP15 stabilized YAP1 by inhibiting the K48-linked ubiquitination of YAP1. In summary, our findings reveal the regulatory role of USP15 in PH progression and provide novel insights into the pathogenesis of PH.

Sympathetic nerves play essential roles in the regulation of lung inflammation, and we investigated the effect of sympathetic denervation (SD) on sepsis-induced acute lung injury (ALI) in mice. Mice were randomized to the control, SD, ALI and SD + ALI, groups. SD and ALI were established through intratracheal 6-hydroxydopamine and intraperitoneal lipopolysaccharide, respectively. Models and gene expressions levels were evaluated by HE staining, ELISA, Western blotting and RT-qPCR. RNA extraction, whole transcriptome sequencing and subsequent biostatistical analysis were performed. Sympathetic denervation in the lungs significantly attenuated lung TNF-ɑ and norepinephrine expression, alleviated sepsis-induced acute lung injury and inhibited NF-κB signaling. Compared with the ALI group, the SD + ALI group exhibited 629 DE circRNAs, 269 DE lncRNAs,7 DE miRNAs and 186 DE mRNAs, respectively. Some DE RNAs were validated by RT-qPCR. CircRNA–miRNA–mRNA regulatory networks in the SD + ALI group revealed enrichment of the B-cell receptor signaling pathway, IL-17 signaling pathway, neuroactive ligand–receptor interaction, CAM, primary immunodeficiency, and cytokine–cytokine receptor interaction terms. The lncRNA-miRNA-mRNA network also revealed inflammation–related signaling pathways. Taken together, based on the successfully established models of SD and ALI, we show here that sympathetic nerves may regulate sepsis-induced ALI supposedly by affecting the expression of circRNAs, lncRNAs, miRNAs, and mRNAs in the lungs. These results may allow for further exploration of the roles of pulmonary sympathetic nerves in sepsis-induced ALI.

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