PT  - JOURNAL ARTICLE
AU  - Shisan Xu
AU  - Fangjing Xie
AU  - Samane Fallah
AU  - Fatemeh Babaei
AU  - Lina Zhu
AU  - Kin Fung Wong
AU  - Yimin Liang
AU  - Rajkumar Ramalingam
AU  - Lei Sun
AU  - Xin Wang
AU  - Yun Wah Lam
AU  - Shuk Han Cheng
TI  - Estrogen accelerates heart regeneration by promoting inflammatory responses in zebrafish
AID  - 10.1101/616250
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 616250
4099  - http://biorxiv.org/content/early/2019/04/23/616250.short
4100  - http://biorxiv.org/content/early/2019/04/23/616250.full
AB  - Sexual differences are frequently observed in the onset and prognosis of human cardiovascular diseases, but the underlying mechanisms are not clearly known. Here, we report that zebrafish heart regeneration is faster in females, can be accelerated by estrogen and suppressed by estrogen-antagonist tamoxifen. Transcriptomic analyses suggested heart injuries triggered more pronounced immune and inflammatory responses, previously shown to enhance heart regeneration, in females, leading to increased STAT1 expression and leukocyte filtration. These responses could be enhanced by estrogen treatment in males. We also showed that injuries to the heart, but not other tissues, increased plasma estrogen level and expression of estrogen receptors, especially esr2a, in zebrafish hearts. Although this effect was stronger in female fish, the resulting endocrine disruption was sufficient to induce the expression of female-specific protein vitellogenin in male zebrafish. Altogether, this study reveals that heart regeneration is modulated by an estrogen-inducible inflammatory response to heart injury, which in turn stimulates estrogen signalling predominately in females. These findings elucidate a previously unknown layer of control in zebrafish heart regeneration and provides a new model system for the study of sexual differences in human cardiac repair.