The Janus face of HMGB1 in heart disease: a necessary update

Angela Raucci,Alessandro D'Ambrosio,Francesco Scavello,Stefania Di Maggio,Marco E Bianchi,Maurizio C Capogrossi

doi:10.1007/s00018-018-2930-9

Abstract

High mobility group box 1 (HMGB1) is a ubiquitous nuclear protein involved in transcription regulation, DNA replication and repair and nucleosome assembly. HMGB1 is passively released by necrotic tissues or actively secreted by stressed cells. Extracellular HMGB1 acts as a damage-associated molecular pattern (DAMPs) molecule and gives rise to several redox forms that by binding to different receptors and interactors promote a variety of cellular responses, including tissue inflammation or regeneration. Inhibition of extracellular HMGB1 in experimental models of myocardial ischemia/reperfusion injury, myocarditis, cardiomyopathies induced by mechanical stress, diabetes, bacterial infection or chemotherapeutic drugs reduces inflammation and is protective. In contrast, administration of HMGB1 after myocardial infarction induced by permanent coronary artery ligation ameliorates cardiac performance by promoting tissue regeneration. HMGB1 decreases contractility and induces hypertrophy and apoptosis in cardiomyocytes, stimulates cardiac fibroblast activities, and promotes cardiac stem cell proliferation and differentiation. Interestingly, maintenance of appropriate nuclear HMGB1 levels protects cardiomyocytes from apoptosis by preventing DNA oxidative stress, and mice with HMGB1cardiomyocyte-specific overexpression are partially protected from cardiac damage. Finally, higher levels of circulating HMGB1 are associated to human heart diseases. Hence, during cardiac injury, HMGB1 elicits both harmful and beneficial responses that may in part depend on the generation and stability of the diverse redox forms, whose specific functions in this context remain mostly unexplored. This review summarizes recent findings on HMGB1 biology and heart dysfunctions and discusses the therapeutic potential of modulating its expression, localization, and oxidative-dependent activities.

Highlights

Cardiac diseases remain a leading cause of morbidity and mortality worldwide [1]
We focus on the recent findings on High mobility group box 1 (HMGB1) redox functions and its role in cardiac dysfunctions
HMGB1 is an ancestral chromatin-binding protein that during evolution has acquired an additional role as an extracellular “alarmin”

Summary

Introduction

Cardiac diseases remain a leading cause of morbidity and mortality worldwide [1]. The adult heart is an organ with limited regenerative potential because of the low ability of cardiomyocytes (CMs) to proliferate after injury [2, 3]. Mice injected with fr-HMGB1 in the ventricular tissue bordering the viable myocardium after MI exhibit improved Left Ventricular (LV) function due to neo-angiogenesis and a partial repopulation of the LV wall by newly formed cardiomyocytes derived from resident cardiac stem cells (CPCs; Fig. 4) [44, 53]. The oxidizing environment generated after MI affects HMGB1 activities, since the injection of the nonoxidizable 3S mutant in infarcted mice worsens cardiac performance and enhances collagen deposition by increasing the number of myofibroblasts This is possibly to a direct and sustained over-activation of CXCR4 (Fig. 4), as 3S is active at lower concentrations relative to fr-HMGB1 and in oxidizing conditions in stimulating hcFb migration and Src phosphorylation [53] (Fig. 3)

Conclusion and future perspective

Findings

Compliance with ethical standards