Hematovascular Biology Center, Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
Department of Cardiovascular Medicine, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan.
Science. 2022 Jul 15;377(6603):292-297. doi: 10.1126/science.abn3100. Epub 2022 Jul 14.
Hematopoietic mosaic loss of Y chromosome (mLOY) is associated with increased risk of mortality and age-related diseases in men, but the causal and mechanistic relationships have yet to be established. Here, we show that male mice reconstituted with bone marrow cells lacking the Y chromosome display increased mortality and age-related profibrotic pathologies including reduced cardiac function. Cardiac macrophages lacking the Y chromosome exhibited polarization toward a more fibrotic phenotype, and treatment with a transforming growth factor β1-neutralizing antibody ameliorated cardiac dysfunction in mLOY mice. A prospective study revealed that mLOY in blood is associated with an increased risk for cardiovascular disease and heart failure-associated mortality. Together, these results indicate that hematopoietic mLOY causally contributes to fibrosis, cardiac dysfunction, and mortality in men.
Y 染色体造血嵌合体丢失（mLOY）与男性的死亡率和与年龄相关疾病的风险增加有关，但因果关系和机制尚未确定。在这里，我们表明，用缺乏 Y 染色体的骨髓细胞重建的雄性小鼠死亡率增加，并且出现与年龄相关的致纤维化病理，包括心脏功能降低。缺乏 Y 染色体的心脏巨噬细胞向更纤维化的表型极化，并且用转化生长因子β1 中和抗体治疗可改善 mLOY 小鼠的心脏功能障碍。一项前瞻性研究表明，血液中的 mLOY 与心血管疾病和心力衰竭相关死亡率的风险增加有关。总之，这些结果表明造血 mLOY 可导致男性纤维化、心脏功能障碍和死亡率增加。
