| First Author | Lazaropoulos MP | Year | 2024 |
| Journal | Nat Cardiovasc Res | Volume | 3 |
| Issue | 7 | Pages | 869-882 |
| PubMed ID | 39196175 | Mgi Jnum | J:359085 |
| Mgi Id | MGI:7782731 | Doi | 10.1038/s44161-024-00502-3 |
| Citation | Lazaropoulos MP, et al. (2024) Nuclear ATP-citrate lyase regulates chromatin-dependent activation and maintenance of the myofibroblast gene program. Nat Cardiovasc Res 3(7):869-882 |
| abstractText | Differentiation of cardiac fibroblasts to myofibroblasts is necessary for matrix remodeling and fibrosis in heart failure. We previously reported that mitochondrial calcium signaling drives alpha-ketoglutarate-dependent histone demethylation, promoting myofibroblast formation. Here we investigate the role of ATP-citrate lyase (ACLY), a key enzyme for acetyl-CoA biosynthesis, in histone acetylation regulating myofibroblast fate and persistence in cardiac fibrosis. We show that inactivation of ACLY prevents myofibroblast differentiation and reverses myofibroblasts towards quiescence. Genetic deletion of Acly in post-activated myofibroblasts prevents fibrosis and preserves cardiac function in pressure-overload heart failure. TGFbeta stimulation enhances ACLY nuclear localization and ACLY-SMAD2/3 interaction, and increases H3K27ac at fibrotic gene loci. Pharmacological inhibition of ACLY or forced nuclear expression of a dominant-negative ACLY mutant prevents myofibroblast formation and H3K27ac. Our data indicate that nuclear ACLY activity is necessary for myofibroblast differentiation and persistence by maintaining histone acetylation at TGFbeta-induced myofibroblast genes. These findings provide targets to prevent and reverse pathological fibrosis. |
