Clin Res Cardiol (2023). https://doi.org/10.1007/s00392-023-02180-w

Dysregulated Klotho/FGF23 signaling exacerbates pulmonary arterial hypertension

P.-L. Perret1, J. H. Lauryn1, C. Ott2, W. Bintig1, T. Funk-Hilsdorf3, S. Simmons4, L. Michalik1, P. Solymosi1, G. Kovacs5, M. Kuro-O6, J. Voelkl7, W. Kübler8, J. Grune1

1CC2: Institut für Physiologie, CCO, Charité - Universitätsmedizin Berlin, Berlin; 2Deutsches Institut für Ernährungsforschung, Nuthetal; 3Charité - Universitätsklinikum Berlin, Institut für Physiologie, Berlin; 4Labor für Lungenkreislaufforschung, Nachwuchsgruppe Immunodynamik, Institut für Physiologie, Charité - Universitätsmedizin Berlin, Berlin; 5Pulmonologie, LKH-Univ. Klinikum Graz - Universitätsklinik für Innere Medizin, Graz, AT; 6Division of Anti-aging Medicine, Jichi Medical University, Shimotsuke, JP; 7Institut für Physiologie und Pathophysiologie, Johannes Kepler Universität Linz, Linz, AT; 8Institut für Physiologie, Deutsches Herzzentrum Berlin, Berlin;

Pulmonary arterial hypertension (PAH)is characterized by an increased mean pulmonary artery pressure (mPAP) >20 mmHg. Key pathological hallmarks of PAH include excessive proliferation of pulmonary vascular smooth muscle cells (PASMCs) and remodeling of small pulmonary arteries, resulting in right ventricular (RV) remodeling and, ultimately, failure. Survival rates of PAH patients remain poor since current therapeutic regimes constitute symptomatic treatment options that do not primarily target lung vascular remodeling. PAH has initially been described as a disease predominantly affecting young women. However, over the past decades the age spectrum of PAH has significantly shifted towards a majority of older or geriatric patients, suggesting age as an additional risk factor in PAH. Aging per se is associated with decreased plasma concentrations of the renal transmembrane protein Klotho, and mice homo- or haplodeficient in klotho demonstrate characteristic signs of premature ageing. Klotho functions as a co-receptor for Fibroblast Growth Factor 23 (FGF23) and thereby regulates cellular functions in multiple tissues. Here, we investigated the role of the Klotho/FGF23 axis in the pathogenesis of age-related PAH. Male C57BL/6 wildtype (WT) mice and klotho-haploinsufficient mice were exposed to chronic hypoxia (10% O2) or normoxia for 14 days to induce experimental PAH. ELISA-based measurements revealed decreased Klotho plasma levels and consequently increased FGF23 plasma levels in Klotho-deficient mice in comparison to WT littermates, which were even more pronounced in Klotho-deficient mice with hypoxia-associated PAH. Klotho/FGF23 dysregulation exacerbated RV systolic pressures (RVSP) of hypoxic mice compared to hypoxic WT controls. Non-invasive small animal echocardiography revealed lower pulmonary artery acceleration time-to-pulmonary artery ejection time ratios (PAT/PET) and faster peak pulmonary artery velocities, known to correlate with PAH severity, in hypoxic Klotho-deficient mice compared to hypoxic WT mice, altogether indicating advanced PAH. Hypoxic Klotho-deficient mice showed increased RV hypertrophy and RV dysfunction compared to hypoxic controls, evident as increased Fulton’s index, and echocardiographically assessed tricuspid annular plane systolic excursion (TAPSE). In line, H&E-stained histological lung cross-sections revealed increased muscularization of small pulmonary arterioles in Klotho-deficient PAH mice compared to hypoxic WT. To probe for a potential direct effect of FGF23 excess on PASMCs, we treated primary PASMCs with recombinant FGF23 and found increased proliferative activity compared to vehicle-treated PASMCs, indicating direct mechanistic involvement of FGF23 excess as a result of klotho-haploinsufficient in pulmonary vascular remodeling in PAH development. In plasma samples of human PAH patients, we were able demonstrate an increase of FGF23 in comparison to healthy individuals. A subgroup analysis revealed significantly higher FGF23 plasma levels in patients aged above 60 years compared to younger patients. We here identify dysregulation of the Klotho/FGF23 axis as a driver of age-related PAH, indicated by exacerbated pulmonary arterial hemodynamics, advanced RV failure, and increased pulmonary vascular remodeling. Targeting dysregulated Klotho/FGF23 signaling might be a promising therapeutic approach to decelerate PAH pathogenesis during aging.

https://dgk.org/kongress_programme/jt2023/aV2031.html