Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA.
Department of Anesthesiology & Perioperative Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Nat Cardiovasc Res. 2024 Jul;3(7):869-882. doi: 10.1038/s44161-024-00502-3. Epub 2024 Jul 5.
Differentiation of cardiac fibroblasts to myofibroblasts is necessary for matrix remodeling and fibrosis in heart failure. We previously reported that mitochondrial calcium signaling drives α-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. TGFβ 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 TGFβ-induced myofibroblast genes. These findings provide targets to prevent and reverse pathological fibrosis.
心肌成纤维细胞向肌成纤维细胞的分化是心力衰竭中基质重塑和纤维化所必需的。我们之前报道过，线粒体钙信号驱动α-酮戊二酸依赖的组蛋白去甲基化，促进肌成纤维细胞的形成。在这里，我们研究了三羧酸循环酶（ACLY）在组蛋白乙酰化调节心肌成纤维细胞命运和在心脏纤维化中持续存在的作用，ACLY 是乙酰辅酶 A 生物合成的关键酶。我们发现，ACLY 的失活可阻止肌成纤维细胞的分化，并使肌成纤维细胞向静止状态逆转。在压力超负荷性心力衰竭中，心肌成纤维细胞激活后敲除 Acly 可防止纤维化并维持心脏功能。TGFβ 刺激增强了 ACLY 的核定位和 ACLY-SMAD2/3 的相互作用，并增加了纤维化基因座处的 H3K27ac。ACLY 的药理学抑制或显性失活 ACLY 突变体的强制核表达可防止肌成纤维细胞的形成和 H3K27ac。我们的数据表明，核 ACLY 活性通过维持 TGFβ 诱导的肌成纤维细胞基因的组蛋白乙酰化对于肌成纤维细胞的分化和持续存在是必需的。这些发现为预防和逆转病理性纤维化提供了靶点。
