GDF11 inhibits cardiomyocyte pyroptosis and exerts cardioprotection in acute myocardial infarction mice by upregulation of transcription factor HOXA3

Zhange Li,Justine Nyakango Mokembo,Han Lou,Seth Mikaye Monayo,Honglin Xu,Lei Wang,Xin Liu,Xue Bai,Nabanit Kumar Jha,Xia Li,Yang Hong,Baofeng Yang,Yong Zhang,Heng Liu

doi:10.1038/s41419-020-03120-6

Abstract

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.

Highlights

Acute myocardial infarction (MI) can lead to sudden cardiac death after prolonged ischemia, and can dispose to heart failure with damaged left ventricle pump function[1,2]
The results revealed that AAV9-GDF11 significantly increased EF% and FS%, compared with the MI group
To further explore whether GDF11 plays an important role in adjusting cardiomyocytes pyroptosis in myocardial infarction, we evaluated the protein levels of NLRP3, ASC, cleaved-caspase-l (c-caspase-1), and GSDMD-N in ischemic heart and hypoxia cardiomyocytes with or without GDF11 treatment

Summary

Introduction

Acute myocardial infarction (MI) can lead to sudden cardiac death after prolonged ischemia, and can dispose to heart failure with damaged left ventricle pump function[1,2]. The inflammatory process is critical for tissue healing, can generate excessive damage and maladjustment of ventricular remodeling, bringing about heart failure and impaired myocardial function[6]. Pyroptosis is an inflammation-dependent type of programmed cell death, which is mediated by inflammasomes[7]. Inflammasomes are signaling transduction protein complexes that are stimulated by endogenous and exogenous stimuli[8,9]. NLRP3 (nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3) inflammasome has been extensively studied[10]. NLRP3 transduces the recognition signal to the adaptor ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) to facilitate activation of caspase-1.

Methods

Results

Conclusion