Neuropeptide Y regulates myocardial fibrosis via NPY1R/JAK2/STAT3 signaling pathway

The level of neuropeptide Y (NPY) is elevated during the pathological progression of heart failure (HF). However, the role and molecular mechanisms of NPY in cardiac fibrosis remain largely uninvestigated. NPY levels were found to be elevated in the serum and fibrotic rat heart tissues after myocardial infarction (MI). Whole-body knock-out NPY (NPY-KO) in rats ameliorated cardiac fibrosis, endothelial mesenchymal transition (EndMT) and cardiac dysfunction and reduced infarct size after myocardial infarction. In contrast, treatment with NPY in rats promoted cardiac fibrosis, EndMT and cardiac dysfunction. Additionally, NPY small interfering RNA (siRNA) in neonatal rat cardiac fibroblasts (CFs) and human coronary artery endothelial cells (HCAECs) reduced fibroblast activation and EndMT in response to TGF-β1 stimulation, while NPY, when given separately, increased fibrotic responses and EndMT-like changes. Bioinformatics and proteome analysis showed that JAK2 (Janus Kinase 2) was mediated by NPY. Further investigation revealed that NPY significantly elevated the expression of NPY receptor Y1 (NPY1R), phosphorylated JAK2 (p-JAK2) and phosphorylated STAT3 (p-STAT3). NPY1R antagonist (BIBO3304) and JAK2/STAT3 inhibitor (WP1066) alleviated cardiac dysfunction, reduced cardiac fibrosis and mitigated EndMT-like changes in rats after NPY administration. Similarly, NPY promoted cell proliferation, collagen production, and EndMT in CFs and HCAECs, whereas BIBO3304 and WP1066 inhibited fibroblast activation and EndMT-like changes induced by NPY. These findings indicate that NPY drives cardiac fibrosis and cardiac dysfunction may be associated with the activation of the NPY1R/JAK2/STAT3 axis, making it a promising therapeutic target to suppress the progression of fibrotic responses.