Hematopoietic loss of Y chromosome leads to cardiac fibrosis and heart failure mortality

• DOI: 10.1126/science.abn3100
• Publication Date: 2022-07-14T17:56:26Z
• Authors: Soichi Sano; Keita Horitani; Hayato Ogawa; Jonatan Halvardson; Nicholas W. Chavkin; Ying Wang; Miho Sano; Jonas Mattisson; Atsushi Hata; Marcus Danielsson; Emiri Miura-Yura; Ammar Zaghlool; Megan A. Evans; Tove Fall; Henry N. De Hoyos; Johan Sundström; Yoshimitsu Yura; Anupreet Kour; Yohei Arai; Mark C. Thel; Yuka Arai; Josyf C. Mychaleckyj; Karen K. Hirschi; Lars A. Forsberg; Kenneth Walsh
• Keywords: Heart Failure; Male; Aging; Mosaicism; Macrophages; Myocardium; Hematopoietic Stem Cells; Antibodies, Neutralizing; Fibrosis; 3. Good health; Mice; Transforming Growth Factor beta; Y Chromosome; Animals; Chromosome Deletion

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.