Reducing branched-chain amino acids improves cardiac stress response in mice by decreasing histone H3K23 propionylation.
Reducing branched-chain amino acids improves cardiac stress response in mice by decreasing histone H3K23 propionylation.
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DOI：
10.1172/jci169399
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发表时间：
2023-11-15
影响因子：
15.9
通讯作者：
Abdellatif, Maha
中科院分区：
文献类型：
--
作者：
Yang, Zhi;He, Minzhen;Austin, Julianne;Sayed, Danish;Abdellatif, Maha
细胞核中支链氨基酸（BCAA）氧化酶的鉴定使我们预测它们是用于组蛋白丙酰化的丙酰辅酶A的来源，从而调节基因表达。为了研究支链氨基酸对心脏肥大和衰竭发展的影响，我们对维持标准水平支链氨基酸饮食（支链氨基酸对照）与不含支链氨基酸饮食的小鼠心脏施加压力超负荷。前者与上调基因启动子处组蛋白H3 K23-丙酰基（H3 K23 Pr）的增加有关（例如，细胞信号传导和细胞外基质基因）和下调基因的启动子的减少（例如，电子转移复合物[ETC I-V]和代谢基因）。有趣的是，不含BCAA的饮食缓和了启动子H3 K23 Pr的增加，从而减少了心脏肥大期间胶原基因的表达和纤维化。相反，不含BCA的饮食抑制了启动子H3 K23 Pr的减少，消除了ETC I-V亚基的下调，增强了线粒体呼吸，并抑制了心脏肥大的进展。因此，降低支链氨基酸的摄入量减少了压力超负荷引起的心脏中组蛋白丙酰化依赖性基因表达的变化，这延缓了心肌病的发展。
Identification of branched-chain amino acid (BCAA) oxidation enzymes in the nucleus led us to predict that they are a source of the propionyl-CoA that is utilized for histone propionylation and, thereby, regulate gene expression. To investigate the effects of BCAAs on the development of cardiac hypertrophy and failure, we applied pressure overload on the heart in mice maintained on a diet with standard levels of BCAAs (BCAA control) versus a BCAA-free diet. The former was associated with an increase in histone H3K23-propionyl (H3K23Pr) at the promoters of upregulated genes (e.g., cell signaling and extracellular matrix genes) and a decrease at the promoters of downregulated genes (e.g., electron transfer complex [ETC I–V] and metabolic genes). Intriguingly, the BCAA-free diet tempered the increases in promoter H3K23Pr, thus reducing collagen gene expression and fibrosis during cardiac hypertrophy. Conversely, the BCAA-free diet inhibited the reductions in promoter H3K23Pr and abolished the downregulation of ETC I–V subunits, enhanced mitochondrial respiration, and curbed the progression of cardiac hypertrophy. Thus, lowering the intake of BCAAs reduced pressure overload–induced changes in histone propionylation–dependent gene expression in the heart, which retarded the development of cardiomyopathy.
影响因子：
3.6
作者：
Suryawan, Agus;Torrazza, Roberto Murgas;Gazzaneo, Maria C.;Orellana, Renan A.;Fiorotto, Marta L.;El-Kadi, Samer W.;Srivastava, Neeraj;Nguyen, Hanh V.;Davis, Teresa A.
通讯作者：
Davis, Teresa A.