Heat shock proteins in atrial fibrillation: from bench to bedside

Abstract

Atrial fibrillation (AF) is the most common age-related arrhythmia in clinic, affecting millions of people around the world, and is closely related to heart failure, ischemic stroke and other diseases. In addition, AF is progressive in nature and represents a significant global health burden. However, the current treatment plans are mainly symptomatic, the efficacy in preventing atrial fibrillation is limited. Hence, there is a pressing need for etiology-specific AF treatments. It is widely acknowledged that the atrial electrical and structural remodeling constitutes the pathological basis of atrial fibrillation. Evidence indicates that heat shock proteins (HSPs) could have a protective effect against AF. HSPs are a diverse family of molecular chaperones that safeguard cells against various stressors. They play a crucial role in mitigating oxidative stress, inflammation, and apoptosis, thereby helping to prevent structural and electrical remodeling in cardiomyocytes. Moreover, HSPs safeguard proteostasis via prevention of toxic protein aggregation by binding to (partially) unfolded proteins. As pivotal inhibitors of AF onset and progression, HSPs represent both a promising therapeutic target and potential biomarkers for staging AF and predicting post-treatment recurrence, as evidenced by recent studies. In this review, we explore the mechanisms of HSP in AF to pave the way for the development of targeted therapies for this prevalent arrhythmia disease.

Keywords: atrial fibrillation; heat shock proteins; inducer; inflammation; oxidative stress; proteostasis.

FIGURE 1

The mechanism by which inflammation and oxidative stress lead to atrial fibrillation. Both the TNF-α/TNFR complex and the ROS system can activate NF-κB in atrial cardiomyocytes. Once activated, NF-κB upregulates NLRP3 inflammasome expression, which directly contributes to the development of AF. Additionally, NF-κB can directly modulate ion channel gene expression by binding to their promoter regions, further influencing atrial electrical and structural remodeling.

FIGURE 2

Illustration of the Role and Mechanism of Heat Shock Proteins (HSPs) in Atrial Myocytes. In response to atrial fibrillation (AF)-related stressors such as oxidative stress and inflammation, the HSP Family—including HSPA, HSPB, HSPC, and HSPD/E—exerts protective (or in some cases, detrimental) effects on atrial cardiomyocytes through a multitude of molecular mechanisms.