Heat shock protein inducer GGA*-59 reverses contractile and structural remodeling via restoration of the microtubule network in experimental Atrial Fibrillation

Abstract

Background: Atrial Fibrillation (AF) is the most common progressive tachyarrhythmia. AF progression is driven by abnormalities in electrical impulse formation and contractile function due to structural remodeling of cardiac tissue. Previous reports indicate that structural remodeling is rooted in derailment of protein homeostasis (proteostasis). Heat shock proteins (HSPs) play a critical role in facilitating proteostasis. Hence, the HSP-inducing compound geranylgeranylacetone (GGA) and its derivatives protect against proteostasis derailment in experimental models for AF. Whether these compounds also accelerate reversibility from structural remodeling in tachypaced cardiomyocytes is unknown. Objective: To investigate whether the potent HSP inducer GGA*-59 restores structural remodeling and contractile dysfunction in tachypaced cardiomyocytes and explore the underlying mechanisms. Materials and results: HL-1 cardiomyocytes post-treated with GGA*-59 or recombinant HSPB1 (rcHSPB1) revealed increased levels of HSPB1 expression and accelerated recovery from tachypacing (TP)-induced calcium transient (CaT) loss compared to non-treated cardiomyocytes. In addition, protein levels of the microtubule protein (acetylated) α-tubulin, and contractile proteins cardiac troponin I (cTnI) and troponin T (cTnT) were reduced after TP and significantly recovered by GGA*-59 or rcHSPB1 post-treatment. The mRNA levels of αtubulin encoding genes, but not cardiac troponin genes, were reduced upon TP and during recovery, but significantly enhanced by GGA*-59 and rcHSPB1 post-treatment. In addition, TP increased calpain activity, which remained increased during recovery and GGA*-59 post-treatment. However, HDAC6 activity, which deacetylates α-tubulin resulting in microtubule disruption, was significantly increased after TP and during recovery, but normalized to control levels by GGA*-59 or rcHSPB1 post-treatment in HL-1 cardiomyocytes. Conclusions: Our results imply that the HSP inducer GGA*-59 and recombinant HSPB1 accelerate recovery from TP-induced structural remodeling and contractile dysfunction in HL-1 cardiomyocytes. GGA*-59 increases HSPB1 levels, represses HDAC6 activity and restores contractile protein and microtubule levels after TP, indicating that HSP-induction is an interesting target to accelerate recovery from AF-induced remodeling.

Evaluating Serum Heat Shock Protein Levels as Novel Biomarkers for Atrial Fibrillation

“…During stress or disease, such as AF, especially, activation of the heat shock transcription factor 1 regulates HSP transcription [ 17 ]. Within the HSP family, small HSPs, including HSP27, are probably the most important in maintaining proteostasis in cardiomyocytes by stabilizing the contractile proteins [ 18 , 19 , 20 , 21 ]. Previously, atrial HSP27 levels were found to be induced in atrial tissue samples of patients with paroxysmal AF, while tissue HSP27 levels get exhausted in patients with (longstanding) persistent AF [ 18 ], indicating that low tissue HSP levels are associated with AF progression.…”

Daily Supplementation of L-Glutamine in Atrial Fibrillation Patients: The Effect on Heat Shock Proteins and Metabolites

“…Various HSPs, including the HSP27 and HSP70, are involved in the protection against different forms of cellular stress by functioning as intra-cellular chaperones for other proteins [6,28]. In cardiomyocytes, HSP27 can bind to structural proteins and thereby shield them from damage and functional loss [6,9,10]. In accordance, upregulation of HSP27 in atrial tissue of dogs protected cardiomyocytes from AF-induced cellular stress and as such contributed to the maintenance of atrial tissue integrity and contractile function [6,28].…”

“…Emerging research findings indicate that heat shock proteins (HSP) mitigate AF onset and progression in experimental model systems for AF [6][7][8][9]. Especially HSP27 (small HSP) has shown promising protective effects against AF in-vitro [10].…”

“…In prior studies, it was shown that L-glutamine enhances translocation of trimerized phosphorylated HSF1 from cytosol to the nucleus, followed by increased DNA binding to heat shock elements in the promotor sequence of hsp genes, thereby resulting in increased HSP expression [20]. Increased HSP expression promotes enhancement of contractile function and prevents loss of cellular integrity during AF [9]. In addition to a role in HSP expression, L-glutamine and its metabolites are important in ATP, DNA and nucleotide formation, suppression of inflammation, attenuation of oxidative stress and apoptosis, and increased blood fluidity and flow [21][22][23][24][25].…”

Cardiac Protective Role of Heat Shock Protein 27 in the Stress Induced by Drugs of Abuse

“…This sensitization results in opening and impairing mitochondrial metabolism through damage of complex I, while calpain inhibition decreases cardiac injury and improves heart function [77,78]. In addition, a recent study shows that post-treatment with the HSP-inducing compound geranylgeranyl acetone increases HSP-27 expression and enhances recovery from tachypacing-induced contractile dysfunction in cardiomyocytes [79]. Several studies have postulated an important role for CRF/CRF1 receptors in anxiety and in somatic, molecular and endocrine alterations evidenced during morphine withdrawal [80,81].…”