α7-nAChR Activation is Associated with Attenuation of Cardiac Fibrosis in Ischemic Cardiomyopathy via SIRT3-Dependent Modulation of EndMT.

To investigate whether α7-nicotinic acetylcholine receptor (α7-nAChR) activation attenuates ischemic cardiomyopathy (ICM) through regulation of endothelial-to-mesenchymal transition (EndMT), and to explore the involvement of Sirtuin-3 (SIRT3) in this process. ICM was induced in rats by coronary ligation for 4 weeks, followed by treatment with PNU-282,987, a selective α7-nAChR agonist, or cardiac-specific SIRT3 knockdown using serotype 9 adeno-associated virus (AAV9). Human umbilical vein endothelial cells (HUVECs) were treated with transforming growth factor-β (TGF-β) and/or PNU-282,987 (10 µM). α7-nAChR activation improved cardiac function, reversed ICM-induced TGF-β upregulation and SIRT3 downregulation, and inhibited EndMT-related changes. These effects were weakened by SIRT3 knockdown. The findings suggest that α7-nAChR activation alleviates ICM and myocardial fibrosis through a SIRT3-dependent mechanism, although direct receptor-level specificity requires further validation.