Redox Aspects of Chaperones in Cardiac Function

Abstract

Molecular chaperones are stress proteins that allow the correct folding or unfolding as well as the assembly or disassembly of macromolecular cellular components. Changes in expression and post-translational modifications of chaperones have been linked to a number of age- and stress-related diseases including cancer, neurodegeneration, and cardiovascular diseases. Redox sensible post-translational modifications, such as S-nitrosylation, glutathionylation and phosphorylation of chaperone proteins have been reported. Redox-dependent regulation of chaperones is likely to be a phenomenon involved in metabolic processes and may represent an adaptive response to several stress conditions, especially within mitochondria, where it impacts cellular bioenergetics. These post-translational modifications might underlie the mechanisms leading to cardioprotection by conditioning maneuvers as well as to ischemia/reperfusion injury. In this review, we discuss this topic and focus on two important aspects of redox-regulated chaperones, namely redox regulation of mitochondrial chaperone function and cardiac protection against ischemia/reperfusion injury.

S-Glutathionylation of human inducible Hsp70 reveals a regulatory mechanism involving the C-terminal α-helical lid

“…Glutathionylation, like phosphorylation, can also regulate cell structure, signal transduction and metabolism, through reversible modulation of the structure and function of specific proteins (34,35). It has been shown that some chaperones are regulated by redox, including Hsp33, Asna1/TRC40, Hsp90, PDI and Hsp27 (36). In addition, Hsp70 and Hsp60 are susceptible to glutathionylation under oxidative stress conditions (36).…”

“…It has been shown that some chaperones are regulated by redox, including Hsp33, Asna1/TRC40, Hsp90, PDI and Hsp27 (36). In addition, Hsp70 and Hsp60 are susceptible to glutathionylation under oxidative stress conditions (36). Glutathionylation of different members of the Hsp70 family has been detected in a variety of cells and tissues under oxidative conditions (21)(22)(23)(24)(25)(26)(27).…”

Phosphorylation Modifications Regulating Cardiac Protein Quality Control Mechanisms

“…There are chaperones that are constitutively expressed (e.g., heat shock cognate 70, HSC70) and others, whose expression are induced by a cardiac stress [e.g., heat shock protein 70 (HSP70)] (Wu et al, 1985;Dworniczak and Mirault, 1987). Chaperones can protect cardiomyocytes against proteotoxicity and subsequent cell death during a stressful/pathological condition Tarone and Brancaccio, 2014;Penna et al, 2018). Indeed, overexpression of certain chaperones has protected hearts from cardiac disease Tarone and Brancaccio, 2014).…”

“…This review highlights the recent advances of arguably the most established PQC-regulating PTM, phosphorylation. Excellent reviews of the other PTMs have been described elsewhere (Christians and Benjamin, 2012;Scruggs et al, 2012;Wang et al, 2013;Penna et al, 2018; VerPlank and Goldberg, 2018). This review details the recent PQC phosphorylations that have been identified ( Supplementary Table 1), especially those with influential roles in cardiac pathophysiology and some ubiquitous signaling pathways, and that can be clinically interrogated.…”

Blocking Extracellular Chaperones to Improve Cardiac Regeneration

“…Chaperones have been originally discovered as induced by hyperthermia, whereby the name of heat shock proteins (HSPs) has been attributed to a number of chaperones (Schlesinger, 1990). Later, it became clear that several chaperones are induced upon different types of stress stimuli, including oxidative stress, pathogen infection, mechanical stress, hypoxic conditions, and ischemia (Sbroggio et al, 2008;Tarone and Brancaccio, 2014;Sorge and Brancaccio, 2016;Penna et al, 2018). Chaperones are divided in different subfamilies depending on their structure, molecular weight and on their ability to hydrolyze ATP (Macario and Conway de Macario, 2005;Kampinga et al, 2009).…”