Insulin-like growth factor binding protein-1 regulates HIF-1\u03b1 degradation to inhibit apoptosis in hypoxic cardiomyocytes

Xiaoyan Tang,Xiaohui Chen,Peiyi Lin,Yi Zhang,Junrong Mo,Huilin Jiang,Ningning Liu,Meiting Chen,Yongcheng Zhu,Zhenhui Zhang

doi:10.1038/s41420-021-00629-3

Abstract

Hypoxia is important in ischemic heart disease. Excessive Insulin-like growth factor binding protein-1 (IGFBP-1) amounts are considered to harm cardiomyocytes in acute myocardial infarction. However, the mechanisms by which IGFBP-1 affects cardiomyocytes remain undefined. The present study demonstrated that hypoxia up-regulates IGFBP-1 and HIF-1α protein expression in cardiomyocytes. Subsequent assays showed that IGFBP-1 suppression decreased HIF-1α expression and inhibited hypoxia-induced apoptosis in cardiomyocytes, which was reversed by HIF-1α overexpression, indicating that HIF-1α is essential to IGFBP-1 function in cellular apoptosis. In addition, we showed that IGFBP-1 regulated HIF-1α stabilization through interacting with VHL. The present findings suggest that IGFBP-1–HIF-1α could be targeted for treating ischemic heart disease.

Highlights

Acute myocardial infarction (AMI) represents the heart disease with the highest morbidity and mortality around the world [1]
1234567890();,: We previously reported that Insulin-like growth factor binding protein-1 (IGFBP-1) amounts are elevated in decreased cell viability in H9c2 cells and CMs under hypoxic the serum of patients with AMI as detected by the antibody array conditions was alleviated by Ad-shIGFBP-1 silencing
As shown Flow cytometry analysis further confirmed that hypoxia-inducible factors (HIFs)-1α overin Fig. 1a and b, IGFBP-1 and HIF-1α were upregulated in hypoxia, expression resulted in enhanced hypoxia-induced apoptosis and which was accompanied by elevated amounts of the apoptotic suppressed the protection afforded by IGFBP-1 knockdown

Summary

INTRODUCTION

Acute myocardial infarction (AMI) represents the heart disease with the highest morbidity and mortality around the world [1]. We of IGFBP-1 potently blocked hypoxia-induced cell death (Fig. 2f utilized neonatal rat ventricular CMs in conjunction with H9c2 cells and Supplementary Fig. 2d). These results indicated that knockas in vitro model, and the AMI model as in vivo model. The aim of down of IGFBP-1 led to decreased HIF-1α protein levels and this study was to establish the molecular role of IGFBP-1 in the protected CMs from apoptosis in hypoxia. Given that IGFBP-1 regulates hypoxia-induced apoptosis and HIF-1α protein expression, we assessed whether IGFBP-1related HIF-1α inhibition is crucial for rescuing cell apoptosis.

RESULTS

Tang et al 3

DISCUSSION

MATERIALS AND METHODS

Findings

ETHICS STATEMENT