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Sano S, Horitani K, Ogawa H, Halvardson J, Chavkin NW, Wang Y, Sano M, Mattisson J, Hata A, Danielsson M, Miura-Yura E, Zaghlool A, Evans MA, Fall T, De Hoyos HN, Sundström J, Yura Y, Kour A, Arai Y, Thel MC, Arai Y, Mychaleckyj JC, Hirschi KK, Forsberg LA, Walsh K
Science (New York, N.Y.) 377 (6603) 292-297 [2022-07-15; online 2022-07-14]
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.
PubMed 35857592
DOI 10.1126/science.abn3100
Crossref 10.1126/science.abn3100