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

Abstract

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/STING inhibition reduced ROS, mtDNA leakage, cGAS-STING activation, senescence markers, and improved diastolic function . In vitro, dual stimulation activated cGAS-STING, induced senescence and SASP secretion, effects attenuated by MAO-A silencing. Conditioned media from senescent H9c2 cells significantly induced cardiac fibroblast activation, as evidenced by increased α-smooth muscle actin; promoted macrophage M1 polarization, indicated by elevated inducible nitric oxide synthase; and triggered an endothelial inflammatory phenotype, characterized by higher vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 expression together with enhanced monocyte adhesion. These effects were partially reversed when MAO-A was silenced in the donor H9c2 cells. Conclusions: MAO-A promotes ROS-dependent cardiomyocyte senescence and diastolic dysfunction in HFpEF via cGAS-STING signaling. Targeting this axis may offer therapeutic benefit in HFpEF.