Ahmed Abdalla, Syed Jibran Nehal, Chi Lijun, Wang Yaxu, Perez-Romero Carmina, Lee Dorothy, Kocaqi Etri, Caballero Amalia, Yang Jielin, Escalante-Covarrubias Quetzalcoatl, Ishimura Akihiko, Suzuki Takeshi, Aguilar-Arnal Lorena, Gonzales Gerard Bryan, Kim Kyoung-Han, Delgado-Olguín Paul
Department of Translational Medicine, The Hospital for Sick Children, Toronto, Ontario Canada.
Department of Molecular Genetics, University of Toronto, Toronto, Ontario Canada.
Nat Cardiovasc Res. 2023;2(2):174-191. doi: 10.1038/s44161-023-00214-0. Epub 2023 Feb 13.
Cardiac metabolism is deranged in heart failure, but underlying mechanisms remain unclear. Here, we show that lysine demethylase 8 (Kdm8) maintains an active mitochondrial gene network by repressing , thus preventing dilated cardiomyopathy leading to lethal heart failure. Deletion of in mouse cardiomyocytes increased H3K36me2 with activation of and repression of target genes in the NAD pathway before dilated cardiomyopathy initiated. NAD supplementation prevented dilated cardiomyopathy in mutant mice, and overexpression blunted NAD-activated cardiomyocyte respiration. Furthermore, was downregulated in human hearts affected by dilated cardiomyopathy, and higher expression defines a subgroup of affected hearts with the strongest downregulation of genes encoding mitochondrial proteins. Thus, KDM8 represses to maintain cardiac metabolism. Our results suggest that epigenetic dysregulation of metabolic gene networks initiates myocardium deterioration toward heart failure and could underlie heterogeneity of dilated cardiomyopathy.
心力衰竭时心脏代谢紊乱，但其潜在机制仍不清楚。在此，我们表明赖氨酸去甲基化酶8（Kdm8）通过抑制来维持活跃的线粒体基因网络，从而预防扩张型心肌病导致致命性心力衰竭。在小鼠心肌细胞中删除在扩张型心肌病发生之前增加了H3K36me2，激活了并抑制了NAD途径中的靶基因。补充NAD可预防突变小鼠的扩张型心肌病，而过表达使NAD激活的心肌细胞呼吸减弱。此外，在受扩张型心肌病影响的人类心脏中下调，较高的表达定义了受影响心脏的一个亚组，其编码线粒体蛋白的基因下调最为强烈。因此，KDM8抑制以维持心脏代谢。我们的结果表明，代谢基因网络的表观遗传失调引发心肌向心力衰竭的恶化，并可能是扩张型心肌病异质性的基础。
