Abstract 4369605: Monoamine Oxidase-A Promotes Cardiomyocyte Senescence and Aggravates Diastolic Dysfunction in HFpEF via cGAS-STING Signaling

作者：Zhuqing Li, Chengzhi Lu, Chunbo Ai · 发表于：Circulation · 年份：2025 · DOI：10.1161/circ.152.suppl_3.4369605 · 研究领域：interferon and immune responses、Cardiac Fibrosis and Remodeling、Congenital heart defects research

Background: Heart failure with preserved ejection fraction (HFpEF) involves myocardial aging, inflammation, and diastolic dysfunction. Monoamine oxidase-A (MAO-A), a mitochondrial enzyme generating reactive oxygen species (ROS), may contribute to cardiac injury, but its role in HFpEF-associated cardiomyocyte senescence is unclear. Hypothesis: Cardiac MAO-A promotes cardiomyocyte senescence via ROS-induced mitochondrial DNA (mtDNA) release and cGAS-STING signaling, exacerbating HFpEF. Methods: Plasma MAO-A activity, circulating mtDNA, and inflammatory cytokines were measured in HFpEF patients and controls. In mice, HFpEF was induced (high-fat diet+l-NAME, 15 wk) in cardiac-specific MAO-A knockout (Maoa^fl/fl; αMHC-Cre) and control littermates, with additional groups receiving MAO-A inhibitor (clorgyline) or STING inhibitor (H-151). Cardiac function, histology, ROS, mtDNA leakage, cGAS-STING activation, and senescence markers were evaluated. In vitro, H9c2 cardiomyoblasts were treated with angiotensin II+high glucose ± MAO-A siRNA. Mitochondrial ROS, cGAS-STING, senescence markers (SA-β-gal, Cdkn2a/Cdkn1a), and senescence-associated secretory phenotype (SASP) secretion were assessed. Conditioned media were used to evaluate fibroblast activation, macrophage polarization, and endothelial inflammation. Results: HFpEF patients had increased MAO-A activity and circulating mtDNA correlating with worse diastolic dysfunction. In mice, cardiomyocyte-specific MAO-A deletion or MAO-A/STIN...