Geroscience. 2026 May 11. doi: 10.1007/s11357-026-02314-8. Online ahead of print.
ABSTRACT
Heart failure with preserved ejection fraction (HFpEF) is a cardiometabolic syndrome strongly associated with aging, systemic inflammation and endothelial dysfunction, in which impaired endothelial nitric oxide synthase (eNOS) signaling plays a central role. This study aimed to identify circulating proteins associated with HFpEF and to explore their relationship with endothelial alterations under metabolic stress. A total of 109 HFpEF patients and 49 control subjects underwent clinical, laboratory, and echocardiographic assessment. HFpEF patients exhibited a high burden of cardiometabolic comorbidities and significantly increased NT-proBNP (2851.2 ± 1565.5 vs 156.0 ± 85.2 pg/mL) and C-reactive protein levels (2.9 ± 4.5 vs 0.31 ± 0.33 mg/dL). Echocardiography revealed elevated filling pressures (E/e’ 16.5 ± 3.8 vs 7.0 ± 1.9), a higher prevalence of high-probability pulmonary hypertension, and impaired right ventricular-pulmonary artery coupling. Exploratory proteomic profiling identified galectin-3 binding protein (LGALS3BP) as increased in plasma from HFpEF patients, a finding confirmed by ELISA showing significantly higher circulating levels compared with controls (8.65 ± 0.66 vs 2.36 ± 0.26 ng/mL, p < 0.001). Pathway analysis suggested a potential association between LGALS3BP and activation of nitric oxide synthase 2 (NOS2)-related inflammatory pathways. In vitro, metabolic stress conditions increased LGALS3BP expression in murine endothelial cells, with a more pronounced response in eNOS⁻/⁻ cells. In addition, eNOS deficiency was associated with the appearance of a lower-molecular weight LGALS3BP form and with increased markers of endothelial senescence and autophagy. LGALS3BP is elevated in HFpEF and is associated with endothelial alterations linked to impaired eNOS signaling under metabolic stress. These findings suggest a potential connection between endothelial stress responses and LGALS3BP expression in HFpEF, supporting further investigation of this protein as a biomarker of endothelial dysfunction in age-related cardiometabolic disease.
PMID:42113325 | DOI:10.1007/s11357-026-02314-8
