Endothelial redox signalling safeguards metabolic and transcriptional integrity and blocks middle-age cardiac hypertrophy
M K Drekolia, E Legchenko, F Delgado Lagos, C Mogler, D Wang, H Cui, I Theodorou, T Vignane, S Guenther, M R Filipovic, B Kojonazarov, I Fleming, J Heineke, J Hu, S I BibliAbstract
Background
Cardiac ageing is characterised by concentric remodelling and metabolic decline. Endothelial dysfunction precedes these changes, yet the specific endothelial signals driving age-related myocardial remodelling remain unclear. Hydrogen sulfide (H2S), generated by cystathionine γ-lyase (CSE), declines with age and regulates vascular redox signalling and metabolism.
Purpose
To determine how endothelial cell (EC)-derived sulfide regulates metabolic and hypertrophic remodelling in the ageing heart and whether restoring H2S availability preserves cardiac structure and function.
Methods
Cardiac sulfide levels, protein persulfidation and H2S generating enzymes were measured from 3 up to 18 month old mice. Cardiac and metabolic health of EC inducible CSE knockdown mice (iEC) and their wild type (WT) littermates were assessed using echocardiography, exhaustion assays (treadmill endurance), pressure-volume (PV) loop and histopathological analyses longitudinally up to 18 months. In vitro, ECs from WT or iEC mice and human CSE-deficient ECs were used in mono-culture or cocultured with murine cardiomyocytes (CM) or human induced pluripotent stem cell (hiPSC) CMs, respectively. EC angiocrine signalling was profiled using proximity-dependent biotin identification (BioID) proteomics. CM phenotype and function were evaluated using transcriptomic, persulfidomic, metabolomic, and ultrastructural analyses. Dietary polysulfide supplementation was initiated at midlife (9 months).
Results
Cardiac sulfides and persulfidation declined in ageing; an effect linked with EC CSE reduction. In vivo, EC CSE loss reduced lifespan and metabolic health, while impaired physical performance. An age-related cardiac decline with reduced cardiac index, concentric hypertrophy with preserved systolic function, worsened relaxation, and early pulmonary dysfunction was observed. Hypertrophy occurred without capillary rarefaction and hiPSC-derived cardiac organoids containing CSE-deficient ECs mimicked these effects. Mechanistically, EC CSE deficiency increased pro-hypertrophic secretion of angiocrines. Among those, a redox-modified isoform, with specific electrophoretic mobility, of the connective tissue growth factor (CTGF) enhanced integrin signalling and triggered CM fetal/hypertrophic transcriptional programmes. In parallel, loss of EC sulfides reduced CM persulfidation resulting in reductive stress, mitochondrial dysfunction, and metabolic collapse in ageing. Remarkably, sulfide supplementation prevented systemic decline and cardiac hypertrophy by restoring metabolic and transcriptional cardiac homeostasis.
Conclusions
EC-derived H2S metabolism is a modifiable regulator of cardiac ageing that maintains CM redox balance, mitochondrial and functional resilience. Restoring sulfide availability in midlife re-establishes EC-CM interactions and delays maladaptive remodelling.