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

How perivascular adipose tissue (PVAT) controls vascular remodeling and perivascular inflammation during pulmonary hypertension progresses remains unknown.

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.

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.

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.