Hematovascular Biology Center, Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA.
Present address: Department of Medicine II, Kansai Medical University, Osaka, Japan.
Nat Cardiovasc Res. 2024 Mar;3(3):343-355. doi: 10.1038/s44161-024-00441-z. Epub 2024 Mar 8.
Heart failure affects millions of people worldwide, with men exhibiting a higher incidence than women. Our previous work has shown that mosaic loss of the Y chromosome (LOY) in leukocytes is causally associated with an increased risk for heart failure. Here, we show that LOY macrophages from the failing hearts of humans with dilated cardiomyopathy exhibit widespread changes in gene expression that correlate with cardiac fibroblast activation. Moreover, we identify the ubiquitously transcribed t et ratricopeptide Y-linked () gene in leukocytes as a causal locus for an accelerated progression of heart failure in male mice with LOY. We demonstrate that disruption leads to epigenetic alterations in both monocytes and macrophages, increasing the propensity of differentiation into profibrotic macrophages. Treatment with a transforming growth factor-β-neutralizing antibody prevented the cardiac pathology associated with deficiency in leukocytes. These findings shed light on the mechanisms that contribute to the higher incidence of heart failure in men.
心力衰竭影响着全球数百万人，男性的发病率高于女性。我们之前的研究表明，白细胞中 Y 染色体的镶嵌缺失（LOY）与心力衰竭风险的增加有因果关系。在这里，我们显示来自扩张型心肌病心力衰竭患者的 LOY 巨噬细胞表现出广泛的基因表达变化，这些变化与心脏成纤维细胞的激活相关。此外，我们鉴定出白细胞中普遍转录的 tetratricopeptide Y 相关（）基因是 LOY 雄性小鼠心力衰竭进展加速的因果基因座。我们证明了 缺失会导致单核细胞和巨噬细胞中的表观遗传改变，增加其向成纤维细胞转化的倾向。用转化生长因子-β中和抗体治疗可以预防白细胞中 缺乏引起的心脏病理。这些发现揭示了导致男性心力衰竭发病率较高的机制。
