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Cardiovascular Research Advance Access originally published online on March 7, 2008
Cardiovascular Research 2008 78(3):422-428; doi:10.1093/cvr/cvn060
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Heat shock proteins as molecular targets for intervention in atrial fibrillation

Bianca J.J.M. Brundel1,2,*, Lei Ke1, Anne-Jan Dijkhuis1, XiaoYan Qi3, Akiko Shiroshita-Takeshita3,4, Stanley Nattel3, Robert H. Henning2 and Harm H. Kampinga1

1 Department of Radiation and Stress Cell Biology, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands
2 Department of Clinical Pharmacology, University Groningen, University Medical Center Groningen, Groningen, The Netherlands
3 Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Canada
4 Department of Emergency and Critical Care Medicine, Keio University School of Medicine, Tokyo, Japan

* Corresponding author. Tel: +31 50 3633399; fax: +31 50 3632913. E-mail address: b.j.j.m.brundel{at}med.umcg.nl

Received 7 December 2007; revised 5 February 2008; accepted 22 February 2008

Time for primary review: 27 days


   Abstract
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Atrial fibrillation (AF) is the most common sustained clinical tachyarrhythmia. AF is a progressive condition as demonstrated by the finding that maintenance of normal rhythm and contractile function becomes more difficult the longer AF exists. AF causes cellular stress, which induces atrial remodelling, involving reduction in the expression of L-type Ca2+ channels and structural changes (myolysis), finally resulting in contractile dysfunction. Heat shock proteins (HSPs) comprise a family of proteins involved in the protection against different forms of cellular stress. Their classical function is the prevention of toxic protein aggregation by binding to (partially) unfolded proteins. Recent investigations reveal that HSPs prevent atrial remodelling and attenuate the promotion of AF in both cellular and animal experimental models. Furthermore, studies in humans suggest a protective role for HSPs against progression from paroxysmal AF to chronic, persistent AF. Therefore, manipulation of the HSP system may offer novel therapeutic approaches for the prevention of atrial remodelling. Such approaches may contribute to the maintenance or restoration of tissue integrity and contractile function. Ultimately, this concept may offer an additional treatment strategy to delay progression towards chronic AF and/or improve the outcome of cardioversion.

KEYWORDS Atrial fibrillation; Heat shock proteins; Geranylgeranylacetone; Hsp27; HspB1; HL-1


   1. Central concepts of atrial remodelling
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Atrial fibrillation (AF) is the most common sustained clinical tachyarrhythmia and a significant contributor to cardiovascular morbidity and mortality.1 AF has the tendency to become more persistent over time.2–4 In addition, the longer the arrhythmia exists, successful pharmacological and electrical cardioversion, including the maintenance of sinus rhythm thereafter, is more difficult.3 Clinical observations show that immediately after cardioversion, atrial contractile function is severely impaired or even absent and recovery of contractile capacity is related to the preceding AF duration.1

Over the past decade, much research has focused on the dissection of mechanisms underlying the progressive nature of AF.1 An important recognition was that AF, once initiated, alters atrial electrophysiological properties in a manner that favours the induction and maintenance of AF.2 A conceptual model for the mechanisms underlying AF progression is depicted in Figure 1. During AF, atrial cardiomyocytes are subjected to very rapid (400–600 times min) and irregular firing, causing an excess Ca2+ entry via the L-type Ca2+ channel into the myocytes.5 The resulting increase in intracellular Ca2+ causes inactivation of the L-type Ca2+ channel. As a result, the action potential shortens and contractile dysfunction develops, enhancing the likelihood of induction and maintenance of AF.6 A second mechanism of early remodelling consists of changes in the activity of specific kinases and phosphatases, resulting in the modulation of key intracellular proteins involved in Ca2+ handling. Recently, it was observed in vitro that the tachypacing-induced decrease in L-type Ca2+ current is caused by activation of key phosphorylation-regulating systems, potentially including CaMKII and calcineurin related pathways.7 Furthermore, indirect evidence suggests that AF-induced changes in the kinomic profile leads to de-phosphorylation of the L-type Ca2+ channel, and consequently reductions in L-type Ca2+ current.8,9 In addition, AF is associated with phosphorylation of phospholamban and ryanodine receptors (RyR2), which might endorse cellular Ca2+ overload.10,11


Figure 1
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  		Figure 1 AF induces time-related atrial remodelling. First, AF causes cardiomyocyte stress, resulting in a rapid cellular Ca2+ overload, which leads to a direct inhibition of the L-type Ca2+ channel. In addition AF induces changes in the kinomic profile leading to indirect inhibition or stimulation of target proteins. Both direct and indirect effects on target proteins result in shortening of action potential duration and loss of contractile function. These processes protect the myocyte against Ca2+ overload but at the expense of creating a substrate for AF and a greater propensity for AF. When the tachycardia persists calcium overload can induce calpain activation. Activated calpain can degrade the L-type Ca2+ channel and contractile proteins resulting in myolysis. During myolysis tissue integrity is maintained, however, at the expense of contractile function. Putative target sites for HspB1 protection against atrial myocyte remodelling are indicated. HspB1 can bind to myofibrils and ion-channels to conserve their function. Furthermore, HspB1 can bind to ion-channels such as L-type Ca2+ channels to protect them from the actions of kinases and/or phosphatases. Alternatively, HspB1 is known to inhibit the activation of cysteine proteases, so HspB1 may inhibit the activation of calpain.

 
When AF persists, tissue adaptive responses in the form of structural remodelling will occur.12,13 This form of tissue adaptation resembles ischemic hibernation and is defined as the ability of the myocytes to turn into a non-functional phenotype by degradation of the myofibril structure (myolysis), which leads to contractile dysfunction.13–16 Cell viability will, however, be maintained for a prolonged period of time, thus ensuring tissue integrity (but not tissue functionality).15 Consequently, myolysis is found in patients with persistent AF and not in patients with exclusively displaying paroxysmal forms of the arrhythmia,12 suggesting a role for myolysis during the end-stage of remodelling.

Previously, it was shown that the cysteine protease calpain represents an important switch between tachycardia-induced Ca2+ overload and atrial remodelling.12,17 The activation of cysteine proteases is widely known to initiate and execute apoptosis.18 However, particularly in cardiac myocytes, apoptosis is not always completed. Depending on the intensity of the stress, activation of cysteine proteases may result in atrial remodelling, by degradation of the L-type Ca2+ channel19,20 or by cleavage of myofilament proteins like cardiac troponin-I, cardiac troponin-T and actin,21–23 leading to shortening of action potential duration, myolysis and contractile dysfunction and hence persistency of AF (Figure 1).


   2. Heat shock proteins: intrinsic protection against atrial remodelling
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Induction of the heat shock response provides cytoprotective effects that may be beneficial in a variety of acute diseases,24 including major cardiac disorders.25 There are at least five main Heat shock protein (HSP) families, small Hsp (HspB), Hsp40 (DnaJB), Hsp60 (HspD), Hsp70 (HspA), and Hsp90 (HspC), each with several family members, (specific) co-factors in various cellular localizations and distinct and overlapping functions (Table 1).26,27 These highly conserved proteins have important roles in protein folding, trafficking and cell signalling.26,28,29 Furthermore, in vitro overexpression of the small Hsp family member HspB1 (Hsp27) enhances alpha-actinin and F-actin stability and recovery after disruption.30,31 The stress-inducible HspA1A (Hsp70) binds and protects the microtubule network and therefore limits myofibril disruption after ischemic stress in myocardium.32 Because of these protective roles of HspB1 and HspA1A against stress-induced cell damage, recent studies have investigated the role of various HSPs in clinical AF by determining the expression levels of HSPs in atrial tissue of patients with paroxysmal and/or persistent AF.33–36 Two independent studies of Yang et al.35 and Brundel et al.33 found elevated HspB1 expression in atrial tissue from patients with paroxysmal AF compared with patients with persistent AF or sinus rhythm. In addition, an inverse correlation was observed between HspB1 expression and the duration of AF and the extent of myolysis.33 Possibly, increased HspB1 expression levels reflect its potential to limit the progression of paroxysmal to persistent AF. Also, two studies reported elevated expression of mitochondrial HSPs, specifically HspD1,34 HspE1 and mortalin (HspA9B) in atrial tissue from patients with AF.37 HspD1 and HspE1 form a mitochondrial chaperonin complex, and a previous study has shown that their increased expression exerts a protective effect against injury when cardiac myocytes are submitted to ischaemia.38 The results indicate that mitochondrial chaperonins HspD1 and HspE1 in combination or individually play an important role in maintaining mitochondrial integrity and capacity for ATP generation, which are the crucial factors in determining survival of cardiac myocytes undergoing ischaemia/reperfusion injury. Therefore, the observed elevated expression of mitochondrial HSPs suggests a protective effect on AF-induced mitochondrial damage, which theoretically could inhibit the progression of AF. To date, however, opposing correlations between the expression of these HSPs and AF have been observed in human persistent AF, including both an induction of HspD1, HspE1 and HspA9B34,37 but also a reduction of HspD1.35


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  		Table 1 Major stress proteins and their protective roles in cardiac diseases

 
Although the above-mentioned studies suggest HSP to inhibit the progression of AF, other studies addressed a protective role of HSP in the development of AF. Both Rammos et al.39 and Mandal et al.40 studied HspA1A expression levels in atrial tissue of patients in sinus rhythm undergoing cardiac surgery. Both studies consistently showed a lower incidence of post-operative AF in patients with higher atrial HspA1A expression levels. In addition, increased HspD1 antibody levels in the serum of patients undergoing CABG were associated with the occurrence of post-operative AF.41 There are indications that HspD1 is increased in the plasma early on the development of heart failure.42–44 Therefore, the observed correlation between HspD1 plasma levels and post-operative AF might reflect the presence of the arrhythmia.

To test more directly whether HSPs indeed protect against AF promoting effects, a tachypaced cell model for AF has been used.17,33,45 In this in vitro model, tachypacing induces the prime features of atrial remodelling, such as suppression of cellular calcium release, L-type Ca2+ current and cell shortening,45 calpain-induced reductions in L-type Ca2+ channel protein amounts, and structural remodelling (myolysis).17 Importantly, pre-induction of HSPs by a mild non-toxic heat shock or by the drug geranylgeranylacetone (GGA) prevented these atrial remodelling processes (Figure 2).33,45 Overexpression or suppression of HspB1 or HspA1A revealed that the protective effect of HSPs is conveyed by the elevated expression of the phosphorylated form of HspB1 and not by HspA1A.33,45 Because of these protective effects in vitro, the protective role of HSPs was studied in a clinically relevant in vivo canine model. There, it was observed that HSP induction by orally administered GGA suppresses AF-related refractoriness abbreviation and AF promotion.45


Figure 2
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  		Figure 2 GGA prevents tachypacing-induced L-type Ca2+ current reductions and APD shortening in isolated canine atrial cardiomyocytes. (A) L-type Ca2+ current was measured in cardiomyocytes paced in vitro at 0, 1 or 3 Hz (P0, P1, P3, respectively) without (CTL, left panel) and with GGA (right panel). Shown is the mean ± SEM L-type Ca2+ current density as a function of test potential during 200-ms depolarizing pulses (0.1 Hz) from –50 mV. (C) Mean ± SEM APD from cardiomyocytes paced for 24 hrs at 1 or 3 Hz (P1, P3, respectively) without (left panel) and with (right panel) GGA. *P < 0.05, **P <0.01, ***P <0.001 vs. P1 cardiomyocytes. (Figure adapted from45 with permission).

 
Although HspB1 was found to be required and sufficient in the prevention of tachypacing-induced atrial remodelling, a recent study in atrial fibroblasts from rats showed HspA1A, induced by a general heat shock, to be involved in the prevention of angiotensin II mediated atrial fibrosis and increased atrial vulnerability to extrastimuli.46 The role of HspA1A on the main characteristics of AF, such as AF promotion (measured as duration of induced AF) and AF vulnerability (percentage of sites at which AF was induced by single premature stimuli) were not studied and therefore no final conclusions concerning a protective role of HspA1A in AF can be drawn yet.


   3. Mode of action of HspB1
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Currently, the exact mode(s) of action by which phosphorylated HspB1 protects from atrial myocyte remodelling is (are) unknown. Mechanistically, there are several possibilities (Figure 1). HspB1 may conserve myofibrils during cardiac stress similar to its protection of cytoskeletal and contractile elements during ischemic stress.30,31,47 In keeping with this mechanism, HspB1 may bind to the myofibril structure, as demonstrated by the (co)-localization of HspB1 with myosin in HL-1 myocytes and at myofilaments in human atrial myocytes.33 Thus, binding of HspB1 to contractile proteins may shield them from AF-induced cleavage by cystein proteases resulting in protection from AF. Further, phosphorylated HspB1, but not unphosphorylated isoforms, stabilize actin filaments and prevent their disruption.48 As actin filament disruption impairs L-type Ca2+ channel function,49 the actin-stabilizing effect of phosphorylated HspB1 may also contribute to preventing atrial tachycardia-induced decrease of L-type Ca2+ current and the associated shortening of action potential duration.

A second mechanism involved in protection from AF by phosphorylated HspB1 is the direct modulation of ion-channel function, resulting in the preservation of the L-type Ca2+ current. Previously, HSPs were implicated in the regulation of ion-channel function in heart and brain.50–53 Some HSPs were found to directly interact with ion-channels, such as HspB5 with Na+ channels,53 HspA1A with cardiac K+ channel hHERG,51 and voltage-gated Ca2+ channels.52 In brain epithelial cells, exogenous administration of HspB1 inhibited the ATP-sensitive and calcium-activated potassium channels.50 Interestingly, studies showed that HSPs, including phosphorylated HspB1, link signal-transduction cascades to (ion-channel) function52,54,55 and this might also apply for the protective effect observed against tachypacing-induced reductions in L-type Ca2+ current. Although it is well known that HspB1 becomes phosphorylated by MAP kinase56 and in this form modulates contraction of intestinal and vascular smooth muscle cells,57 the exact role of HspB1 in modulating the activation of kinases or phosphatases is unknown. HspB1 interacts with certain (downstream) kinases, such as IkappaB kinase and c-Jun N-terminal kinase (JNK), thereby suppressing activation of the transcription factor NF-kappaB.58,59 Interestingly, these kinases have also been found to be modulated during AF.60,61

Finally, HspB1 might prevent myocyte remodelling via inhibition of calpain. Although no studies have described the modulation of calpain by HspB1, HspB1 was found to modulate in vitro other cystein proteases such as caspase 3.62

Thus, based on the current knowledge of HspB1, the principle candidates for its mode of action in AF include prevention of the activation of the cysteine protease calpain, prevention of changes in kinomics and inhibition of the degradation of myofibrils.


   4. Heat shock protein modulation as a novel therapeutic approach in atrial fibrillation
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As the protective action of HSPs depends on their timely induction, drugs that boost endogenous heat shock responses, such as GGA and bimoclomol, may be of particular interest in AF.63–66

Pharmacological approaches to preventing atrial remodelling are being studied, with the hope that they might be useful therapeutic agents in treating AF.67 So far, the efficacy of commonly used drugs on remodelling is limited, as L-type Ca2+ channel blockers, Na+/H+ exchange inhibitor and an angiotensin-converting enzyme inhibitor are ineffective in preventing remodelling caused by prolonged (>24 h) periods of atrial tachycardia.68 Drugs with T-type Ca2+ channel blocking action, such as mibefradil69 and amiodarone70 prevent atrial tachycardia remodelling, although both also have a wide range of other properties so that the precise mechanism for their benefit is unclear. Interventions with anti-inflammatory and/or antioxidant actions, such as glucocorticoids71 and statins72 prevent atrial remodelling and may have some efficacy in clinical AF.73,74 Interestingly, glucocorticoids and statins induce HspB1 expression and phosphorylation75,76, leaving open the possibility that the protective effect of these drugs is due to (co-)inducing properties of HspB1 (Table 2).


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  		Table 2 HSP inducing compounds for the heart

 
Consequently, HSP (co-)inducers may represent a novel anti-remodelling intervention in AF. A drug often used for boosting HSP expression is GGA, an anti-ulcer agent (Table 2).77 GGA is a non-toxic acyclic isoprenoid compound with a retinoid skeleton that induces HSP synthesis in various tissues, including gastric mucosa, intestine, liver, myocardium, retina, and central nervous system.65,66,77 GGA induces HSP expression through activation of the heat shock transcription factor HSF1.77,78 Oral administration of GGA rapidly upregulates general HSP expression in response to a variety of stresses, whereas its effect is weaker under non-stress conditions.79

In HL-1 atrial myocytes, GGA protects against atrial remodelling induced by tachypacing, including the degradation of myofibrils,33 the suppression of cellular Ca2+-induced Ca2+ release, and the loss of cell contractility.45 In addition, in a clinically relevant canine model for AF, orally administered GGA protects against AF-induced atrial remodelling.45 Furthermore, it has also been observed that GGA protects against AF-promoting atrial remodelling of different origins (Figure 3). In vivo experiments revealed that HSP induction by GGA treatment attenuates atrial structural remodelling and AF promotion in canine models of congestive heart failure and acute ischaemia-induced AF.80,81 The protective effects of GGA against AF-related atrial remodelling suggests that inducers of the heat shock response have potential therapeutic value for clinical AF. Although various compounds modulate HSP expression and have been found to protect against ischaemic heart diseases (Table 2), their therapeutic efficacy in AF is yet unknown.


Figure 3
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  		Figure 3 Tachycardia, congestive heart failure (CHF), acute ischemia and (frequently) cardiac surgery induce atrial remodelling which is a substrate for the promotion of AF. The HSP (co)-inducer GGA prevents atrial remodelling and the promotion of AF of different origin. Tachypacing-induced atrial remodelling is also prevented by a mild heat shock or the overexpression of HspB1.

 
In summary, during AF, the high rate of myocyte activation causes cellular stress and hence activates the atrial remodelling processes, which paradoxically promote persistency of AF. There are strong indications that HSPs, and in particular HspB1, prevents against AF-induced and other forms of AF-related atrial remodelling and therefore suppress the promotion of AF. Utilization of HSPs offers a novel therapeutic strategy in AF, directed at maintaining or restoring tissue integrity and contractile function. Dissection of the molecular mechanism by which HSPs protect myocytes from remodelling may identify more specific therapeutic interventions. Ultimately, inducers of HSPs may add to the therapeutic armament to delay progression towards persistent AF and/or improve the outcome of cardioversion in man.


   5. Funding
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This study was financed by the Dutch Organization for Scientific Research (NWO program grant 916. 46. 043), Ubbo Emmius Bursaal grant from the University of Groningen (Number 800403), Angteq/Kop grant (H2514NL00), the Canadian Institutes of Health Research, the Quebec Heart and Stroke Foundation and the Mathematics of Information Technology and Complex Systems (MITACS) Network of Centers.


   Acknowledgements
 
We thank Dr Dirkjan Masman for critical comments on the manuscript and Jurre Hageman and Michel Vos for excellent assistance with the characterization of the HSP family members.

Conflict of interest. none declared.


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