Cardiomyocyte-restricted high-mobility group box 1 (HMGB1) deletion leads to small heart and glycolipid metabolic disorder through GR/PGC-1\u03b1 signalling

Peng Yu,Junbo Ge,Yunzeng Zou,Lei Zhang,Ming Liu,Shiyao Xie,Enyong Su,Ying Yu,Xue Yang,Baoli Zhang,Hong Jiang,Ruizhen Chen

doi:10.1038/s41420-020-00340-9

Abstract

Cardiac growth and remodelling are key biological processes influencing the physiological performance of the heart, and a previous study showed a critical role for intracellular HMGB1 in vitro. However, the in vivo study, which used conditional Hmgb1 ablation, did not show a significant effect on cellular or organic function. We have demonstrated the extracellular effect of HMGB1 as a pro-inflammatory molecule on cardiac remodelling. In this study, we found that HMGB1 deletion by cTnT-Cre in mouse hearts altered glucocorticoid receptor (GR) function and glycolipid metabolism, eventually leading to growth retardation, small heart and heart failure. The subcellular morphology did not show a significant change caused by HMGB1 knockout. The heart showed significant elevation of glycolysis, free fatty acid deposition and related enzyme changes. Transcriptomic analysis revealed a list of differentially expressed genes that coincide with glucocorticoid receptor function in neonatal mice and a significant increase in inflammatory genes in adult mice. Cardiac HMGB1 knockout led to a series of changes in PGC-1α, UCP3 and GyK, which were the cause of metabolic changes and further impacted cardiac function. Ckmm-Cre Hmgb1fl/fl mice did not show a specific phenotype, which was consistent with the reported negative result of cardiomyocyte-specific Hmgb1 deletion via MHC-Cre. We concluded that HMGB1 plays essential roles in maintaining normal cardiac growth, and different phenotype from cardiac-specific HMGB1-deficient mice may be caused by the cross with mice of different Cre strains.

Highlights

Cardiac growth and remodelling are key biological processes influencing the physiological performance of the heart
We further exclude the leakage of the cardiac Troponin T (cTnT)-Cre mice using western blot to detect High-mobility group box 1 (HMGB1) in the liver, spleen, lung, kidney, muscle, ovary and testis, which showed no difference between the two groups (Fig. S1e)
We found that deletion of HMGB1 led to impaired heart growth and left ventricular dysfunction, accompanied by a dramatic decrease in body weight

Summary

Introduction

Cardiac growth and remodelling are key biological processes influencing the physiological performance of the heart. Cardiomyopathy is one of the most common causes of heart failure and is characterized by cardiac remodelling and contractile dysfunction. High-mobility group box 1 (HMGB1), which exhibits diverse biological functions depending on cellular location, is a non-histone DNA-binding nuclear protein present in most cell types[2]. Intracellular HMGB1 regulates autophagy, facilitates DNA repair and regulates transcriptional regulation[3,4,5]. In vivo validation of the versatile functions of HMGB1 shows its dispensable role in adult organisms[6]. Newborn Hmgb1deficient mice exhibited lethal hypoglycaemia[7,8]. Mice of different Cre strains could lead to diverse phenotypes

Methods

Results

Conclusion