Adipokine Nesfatin-1 Mediates Endothelial Dysfunction by Suppressing MEF2B/BMPR1A During Pulmonary Vascular Remodeling

BACKGROUND: How perivascular adipose tissue (PVAT) controls vascular remodeling and perivascular inflammation during pulmonary hypertension progresses remains unknown. METHODS: Western blotting, ELISA, immunohistochemistry, and immunofluorescence were used to measure proteins expression. Sugen 5416 combined with hypoxia (SuHx) mouse models were established in C57BL/6 mice, and treated with CL-316243. Adeno-associated virus vector delivery was used to specifically delete nesfatin-1 in adipocytes of lung in mice. Transthoracic echocardiography was performed to evaluate the function of right ventricle. Assays for cell angiogenesis and adhesion were used to analyze endothelial cell function. A noncontact transwell coculture model was used to evaluate the interaction between different types of cells. RESULTS: PVAT dysfunction participates in SuHx-induced pulmonary vascular remodeling, PVAT exhibits features of white adipose tissue and the adipocytokine nesfatin-1 is the key mediator. Browning of white adipose tissue via CL-316243 treatment attenuates pulmonary hypertension phenotype in a SuHx-pulmonary hypertension mouse model. Specific deletion of nesfatin-1 in adipocytes of lung attenuates SuHx-induced pulmonary vascular remodeling. Nesfatin-1 secretion is induced by IL-17/Th17 via PI3K/AKT/mTOR pathway. In vitro, nesfatin-1 promotes angiogenesis, adhesion, and apoptosis of endothelial cells. Coculture with 3T3-L1 adipocytes promotes endothelial dysfunction mediated by nesfatin-1. Mechanistic research shows that nesfatin-1 mediates endothelial dysfunction by downregulating BMPR1A expression via MEF2B at the transcriptional and posttranslational levels. CONCLUSIONS: PVAT dysfunction participates in pulmonary vascular remodeling through nesfatin-1-mediated endothelial dysfunction, suggesting that PVAT and nesfatin-1 may constitute novel therapeutic targets for pulmonary hypertension.