Heart failure & cardiomyopathies
SIRT5 Ameliorates Cardiac Fibrosis via PCK2 Desuccinylation-Mediated Metabolic Reprogramming in Cardiac Fibroblasts
Authors' conclusion
By desuccinylating PCK2 at Lys489, SIRT5 prevents the metabolic reprogramming and subsequent activation of CFBs, protecting against cardiac fibrosis.
Study context
- Population
- Humans and mice with HF; mice subjected to transverse aortic constriction
- Comparison
- Cardiac fibroblast (CFB)-specific Sirt5 knockout or overexpression vs control in TAC-induced cardiac fibrosis
Methodological detailshuman and mouse HF cardiac tissue, CFB-specific Sirt5 knockout and overexpression mice, Pck2 K489R mutation
- Human and mouse HF cardiac tissue
- CFB-specific Sirt5 knockout and overexpression mice
- Pck2 K489R mutation
Main finding
As reported in the abstract
- SIRT5 expression markedly reduced in CFBs from humans and mice with HF; negative correlation with cardiac fibrosis severity
- Loss of Sirt5 in CFBs exacerbated LV dysfunction, cardiac hypertrophy and fibrosis after transverse aortic constriction; Sirt5 overexpression significantly attenuated these changes
- Sirt5 deficiency promoted CFB activation via metabolic shift from oxidative phosphorylation to glycolysis
- Sirt5 deficiency increased PCK2 succinylation at Lys489, inhibiting its enzyme activity
- Succinylation-preventing Lys489 mutation reversed metabolic reprogramming and CFB hyperactivation after Sirt5 knockout
- In vivo Pck2 K489R mutation fully rescued exacerbated cardiac fibrosis and dysfunction in Sirt5-deficient mice after transverse aortic constriction
Original publication
SIRT5 Ameliorates Cardiac Fibrosis via PCK2 Desuccinylation-Mediated Metabolic Reprogramming in Cardiac Fibroblasts. Circulation. Published 23 April 2026. doi:10.
Summarised from the published abstract; every number is checked against it