Estrogen accelerates heart regeneration by promoting the inflammatory response in zebrafish

Sexual differences have been observed in the onset and prognosis of human cardiovascular diseases, but the underlying mechanisms are not clear. Here, we found that zebrafish heart regeneration is faster in females, can be a ccelerated by estrogen and is suppressed by the estrogen-antagonist tamoxifen. Injurie s to the zebrafish heart, but not other tissues, increased plasma estrogen levels and the expression of estrogen receptors, especially esr2 alpha. The resulting endocrine disruption induces the expression of the female-specific protein vitellogenin in male zebrafish. Tr anscriptomic analyses suggested heart injuries triggered pronounced immune and inflamm atory responses in females. These responses, previously shown to elicit heart regeneration, could be enhanced by estrogen treatment in males and reduced by tamoxifen in females. Furthermore, a prior exposure to estrogen preconditioned the ze brafish heart for an accelerated regeneration. Altogether, this study reveals that heart regeneration is modulated by an estrogen-inducible inflammatory response to card iac injury. These findings elucidate a previously unknown layer of control i n zebrafish heart regeneration and provide a new model system for the study of se xual differences in human cardiac repair.