The protective role of small heat shock proteins in cardiac diseases: key role in atrial fibrillation

Abstract

Atrial fibrillation (AF) is the most common tachyarrhythmia which is associated with increased morbidity and mortality. AF usually progresses from a self-terminating paroxysmal to persistent disease. It has been recognized that AF progression is driven by structural remodeling of cardiomyocytes, which results in electrical and contractile dysfunction of the atria. We recently showed that structural remodeling is rooted in derailment of proteostasis, i.e., homeostasis of protein production, function, and degradation. Since heat shock proteins (HSPs) play an important role in maintaining a healthy proteostasis, the role of HSPs was investigated in AF. It was found that especially small heat shock protein (HSPB) levels get exhausted in atrial tissue of patients with persistent AF and that genetic or pharmacological induction of HSPB protects against cardiomyocyte remodeling in experimental models for AF. In this review, we provide an overview of HSPBs as a potential therapeutic target for normalizing proteostasis and suppressing the substrates for AF progression in experimental and clinical AF and discuss HSP activators as a promising therapy to prevent AF onset and progression.

Keywords: Atrial fibrillation; Heat shock protein; Proteostasis; Small HSP (HSPB).

Fig. 1

AF induces a calcium overload in cardiomyocytes, which activates calcium-dependent neutral protease calpain. Calpain degrades contractile proteins and microtubule network resulting in structural remodeling, contractile dysfunction of cardiomyocytes, and AF progression. Elevated HSPB1 is found to inhibit calpain activity in tachypaced Drosophila. In addition, HSPB1 prevents degradation of cardiac troponins and may protect against depolymerization of α-tubulin by sequestering the proteolytic cleavage sites from calpain