Abstract: Heart failure with preserved ejection fraction (HFpEF) remains a clinical challenge lacking effective therapies. While Cannabidiol (CBD) suggests cardioprotective potential, its efficacy and underlying in HFpEF are poorly understood. This study investigated the effects of CBD on a murine model of HFpEF induced by a high-fat diet and L-NAME for 8 weeks. CBD was administered subcutaneously every three days. Hemodynamic performance was assessed via invasive pressure¿volume loops, complemented by histological analysis and oxidative stress markers. Cellular senescence, NLRP3-mediated inflammation and Mitochondria-Endoplasmic Reticulum Contact Sites (MERCSs) were evaluated through immunofluorescence, RT-qPCR, and transmission electron microscopy. CBD treatment failed to reduce cardiac hypertrophy but improves cardiac fibrosis and diastolic dysfunction. These improvements were associated with a marked reduction in senescent cells accumulation and on systemic cytokine levels that may be associated with the senescence-associated secretory phenotype (SASP). Notably, CBD suppressed the NLR3-mediated proinflammatory state by preserving inter-organelle distance and MERCSs integrity. Our findings demonstrate, for the first time, that CBD modulates MERCSs communication to regulate senescence and inflammation in HFpEF. These results position CBD as a promising intervention for mitigating the pathology of HFpEF through the regulation of MERCSs, although the signaling pathways involved in this protective mechanism need to be characterized.
