Macrophage-specific SPP1 overexpression in mice increased atrial fibrillation inducibility and duration significantly compared to controls (p < 0.05).
Do SPP1+ macrophages induce cardiomyocyte apoptosis and promote atrial fibrillation susceptibility?
SPP1+ macrophages promote atrial fibrillation susceptibility by inducing cardiomyocyte apoptosis via downregulation of the PI3K/AKT pathway, highlighting a potential therapeutic target.
Effect estimate: AF inducibility significantly increased (p < 0.05); AF duration significantly increased (p < 0.05)
Absolute Event Rate: 100% vs 50%
p-value: p=<0.05
Atrial fibrillation (AF) is closely linked to atrial remodeling, while its underlying immune mechanisms remain elusive. This study sought to investigate the role of SPP1+ macrophages in the development and progression of AF and further elucidate the underlying mechanisms. Single-nucleus RNA sequencing was performed on right atrial tissues from 3 patients with persistent AF and 3 with sinus rhythm (all with rheumatic valvular heart disease). The results revealed significant immune cell infiltration in AF atrial tissues, with a marked increase in the proportion of SPP1+ macrophages, which exhibited the strongest intercellular communication with cardiomyocytes. Phenotypic scoring indicated that apoptosis was the dominant mode of cardiomyocyte death in AF. Immunohistochemical and Western blot analyses confirmed elevated levels of pro-apoptotic proteins (Bax, Cleaved-Caspase3) and reduced levels of the anti-apoptotic protein Bcl2 in AF tissues. In a mouse model with macrophage-specific SPP1 overexpression, increased AF inducibility and duration were observed, accompanied by enhanced cardiomyocyte apoptosis. In vitro co-culture experiments using SPP1-overexpressing RAW264.7 macrophages and HL-1 cardiomyocytes confirmed that SPP1+ macrophages could induce cardiomyocyte apoptosis. Mechanistically, KEGG and GSEA analyses identified downregulation of the PI3K/AKT pathway in AF. Treatment with the PI3K/AKT activator Recilisib reversed apoptosis and restored p-PI3K/p-AKT levels in HL-1 cells co-cultured with SPP1-overexpressing RAW264.7 macrophages. These findings demonstrate that SPP1+ macrophages accumulate in atrial tissues of AF patients and induce cardiomyocyte apoptosis by downregulating the PI3K/AKT pathway, thereby increasing AF susceptibility.
Wang et al. (Thu,) conducted a other in Patients with rheumatic valvular heart disease undergoing mitral valve replacement surgery, with persistent atrial fibrillation or sinus rhythm (n=10). Macrophage-specific SPP1 overexpression via AAV9 vector (HBAAV2/9-F4/80-m-Spp1-3xflag-mcherry) in mice vs. Wild-type mice and negative control mice injected with control AAV9 vector was evaluated on Atrial fibrillation inducibility and duration after programmed electrical stimulation (AF inducibility significantly increased (p < 0.05); AF duration significantly increased (p < 0.05), p=<0.05). Macrophage-specific SPP1 overexpression in mice increased atrial fibrillation inducibility and duration significantly compared to controls (p < 0.05).