Bmp10 is essential for cardiovascular function by maintaining the systematic iron homeostasis

Heart failure is a leading cause of death globally, and iron metabolism disorder is an important cause of anemia and heart failure. However, the exact role of iron in heart failure is unclear. Here, we discovered and demonstrated that bmp10, Bone Morphogenetic protein 10, can regulate iron metabolism. The mutation of bmp10 caused severe anemia and cardiac hypertrophy with protruded and falling scales, abdominal edema, skin hemorrhage and stunted body size, which died ultimately. RNA-seq analysis revealed dysregulation of iron metabolism in the bmp10-/- zebrafish. As a result, bmp10 deficiency results in systematic iron dysregulation and ferroptosis in zebrafish heart. Most importantly, both iron supply and iron chelation could improve the survival of bmp10-/- zebrafish, alleviated hypertrophy and ferroptosis. Further investigation revealed that bmp10-/- zebrafish suffered a chronic inflammatory anemia at the late stage with reduced total iron binding capacity (TIBC) and sluggish response of epoa. Meanwhile, the bmp10-/- mutant heart suffer inflammation response with elevated IL6 expression. Correspondingly, the loss of bmp10 caused shift in hepcidin concentrations through the hypoxic response and IL6/JAK/STAT3 pathway, resulting in iron-overload in late stage, which in turn promote a progressive lipid peroxidation from earlier to latter stage with higher MDA and ROS level, leading to cardiac damage and subsequent heart failure. In addition, bmp10 functions similarly in H9C2 cell suggesting the iron regulatory function of bmp10 is conserved in mammalian cardiac cells. These findings highlight that bmp10 play an important role in iron metabolism, and regulation the expression of bmp10 may be useful as a protective strategy in anemia and heart failure.