Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, 150081, China.
Department of Pharmacology and Therapeutics, Melbourne School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences University of Melbourne, Melbourne, VIC, 3010, Australia.
Cell Death Dis. 2020 Oct 25;11(10):917. doi: 10.1038/s41419-020-03120-6.
NLRP3 (Nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3) inflammasome-mediated cardiomyocytes pyroptosis plays a crucial part in progression of acute myocardial infarction (MI). GDF11 (Growth Differentiation Factor 11) has been reported to generate cytoprotective effects in phylogenesis and multiple diseases, but the mechanism that GDF11 contributes to cardioprotection of MI and cardiomyocytes pyroptosis remains poorly understood. In our study, we first determined that GDF11 was abnormally downregulated in the heart tissue of MI mice and hypoxic cardiomyocytes. Moreover, AAV9-GDF11 markedly alleviated heart function in MI mice. Meanwhile, GDF11 overexpression also decreased the pyroptosis of hypoxic cardiomyocytes. PROMO and JASPAR prediction software found that transcription factor HOXA3 was predicted as an important regulator of NLRP3, and was confirmed by ChIP assay. Further analysis identifying GDF11 promoted the Smad2/3 pathway resulted in HOXA3 overexpression. Taken together, our study implies that GDF11 prevents cardiomyocytes pyroptosis via HOXA3/NLRP3 signaling pathway in MI mice.
NLRP3（核苷酸结合寡聚化结构域样受体pyrin 结构域包含 3）炎性小体介导线粒体细胞焦亡在急性心肌梗死（MI）的进展中起着关键作用。GDF11（生长分化因子 11）已被报道在系统发生和多种疾病中产生细胞保护作用，但 GDF11 对 MI 和心肌细胞焦亡的心脏保护作用的机制仍知之甚少。在我们的研究中，我们首先确定 GDF11 在 MI 小鼠和缺氧心肌细胞的心脏组织中异常下调。此外，AAV9-GDF11 显著改善了 MI 小鼠的心脏功能。同时，GDF11 的过表达也降低了缺氧心肌细胞的焦亡。PROMO 和 JASPAR 预测软件发现转录因子 HOXA3 被预测为 NLRP3 的重要调节因子，并通过 ChIP 实验得到了证实。进一步的分析确定 GDF11 促进 Smad2/3 通路导致 HOXA3 的过表达。综上所述，我们的研究表明，GDF11 通过 HOXA3/NLRP3 信号通路防止 MI 小鼠的心肌细胞焦亡。
