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      Response of circulating heat shock protein 70 and anti-heat shock protein 70 antibodies to catheter ablation of atrial fibrillation

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          Abstract

          Background

          This pilot study investigated the association between heat shock protein 70 (HSP70) and anti-HSP70 antibodies as well as their changes and rhythm outcome after atrial fibrillation (AF) catheter ablation.

          Methods

          We studied 67 patients with AF (59±11 years, 66% male, 66% lone AF) undergoing catheter ablation. Circulating HSP70 and anti-HSP70 antibody levels were quantified using commercially available assays before and 6 months after catheter ablation. Serial 7-day Holter ECGs were used to detect AF recurrences.

          Results

          At baseline, HSP70 was detectable in 14 patients (21%), but there was no correlation between clinical or echocardiographic variables and the presence or the level of HSP70. In contrast, patients with paroxysmal AF (n=39) showed lower anti-HSP70 antibodies (median [IQR] of 43 [28 – 62] μg/ml) than patients with persistent AF (n=28; 53 [41 – 85] μg/ml, p=0.035). Using multivariable regression analysis, AF type was the only variable associated with anti-HSP70 antibodies (Beta=0.342, p=0.008). At 6 months, HSP70 was present in 27 patients (41%, p<0.001 vs. baseline). Similarly, there was an increase of anti-HSP70 antibodies (48 [36 – 72] vs. 57 [43 – 87] μg/ml, p<0.001). AF recurrence rates were higher in patients with HSP70 increase ≥0.025 ng/ml (32 vs. 11%, p=0.038) or anti-HSP70 increase ≥2.5 μg/ml (26 vs. 4%, p=0.033).

          Conclusions

          HSP70 and anti-HSP70 antibodies may – at least in part – be associated in the progression of AF and AF recurrence after catheter ablation.

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          Most cited references27

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          HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine.

          Here, we demonstrate a previously unknown function for the 70-kDa heat-shock protein (HSP70) as a cytokine. HSP70 bound with high affinity to the plasma membrane, elicited a rapid intracellular calcium flux, activated nuclear factor (NF)-kappaB and upregulated the expression of pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6 in human monocytes. Furthermore, two different signal transduction pathways were activated by exogenous HSP70: one dependent on CD14 and intracellular calcium, which resulted in increased IL-1beta, IL-6 and TNF-alpha; and the other independent of CD14 but dependent on intracellular calcium, which resulted in an increase in TNF-alpha but not IL-1beta or IL-6. These findings indicate that CD14 is a co-receptor for HSP70-mediated signaling in human monocytes and are indicative of an previously unrecognized function for HSP70 as an extracellular protein with regulatory effects on human monocytes, having a dual role as chaperone and cytokine.
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            HSP70 as endogenous stimulus of the Toll/interleukin-1 receptor signal pathway.

            Human heat-shock protein (HSP)70 activates innate immune cells and hence requires no additional adjuvants to render bound peptides immunogenic. Here we tested the assumption that endogenous HSP70 activates the Toll/IL-1 receptor signal pathway similar to HSP60 and pathogen-derived molecular patterns. We show that HSP70 induces interleukin-12 (IL-12) and endothelial cell-leukocyte adhesion molecule-1 (ELAM-1) promoters in macrophages and that this is controlled by MyD88 and TRAF6. Furthermore, HSP70 causes MyD88 relocalization and MyD88-deficient dendritic cells do not respond to HSP70 with proinflammatory cytokine production. Using the system of genetic complementation with Toll-like receptors (TLR) we found that TLR2 and TLR4 confer responsiveness to HSP70 in 293T fibroblasts. The expanding list of endogenous ligands able to activate the ancient Toll/IL-1 receptor signal pathway is in line with the "danger hypothesis" proposing that the innate immune system senses danger signals even if they originate from self.
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              Role of the cytosolic chaperones Hsp70 and Hsp90 in maturation of the cardiac potassium channel HERG.

              The human ether-a-gogo-related gene (hERG) encodes the alpha subunit of the cardiac potassium current IKr. Several mutations in hERG produce trafficking-deficient channels that may cause hereditary long-QT syndrome and sudden cardiac death. Although hERG currents have been studied extensively, little is known about the proteins involved in maturation and trafficking of hERG. Using immunoprecipitations, we show that the cytosolic chaperones heat shock protein (Hsp) 70 and Hsp90, but not Grp94, interact with hERG wild type (WT) during maturation. The specific Hsp90 inhibitor geldanamycin prevents maturation and increases proteasomal degradation of hERG WT, while reducing hERG currents in heterologous expression systems. In ventricular myocytes, inhibition of Hsp90 also decreases IKr, whereas geldanamycin had no effect on IKs or heterologously expressed Kv2.1 and Kv1.5 currents. Both Hsp90 and Hsp70 interact directly with the core-glycosylated form of hERG WT present in the endoplasmic reticulum but not the fully glycosylated, cell-surface form. For the trafficking-deficient LQT2 mutants, hERG R752W and hERG G601S, interactions with Hsp90 and Hsp70 are increased as both mutants remained tightly associated with Hsp90 and Hsp70 in the endoplasmic reticulum. Incubation at lower temperature for R752W or with the hERG blocker astemizole for G601S dissociates channel-chaperone complexes and restores trafficking. In contrast, nonfunctional but trafficking-competent hERG G628S is released from chaperone complexes during maturation comparable to WT. We conclude that Hsp90 and Hsp70 are crucial for the maturation of hERG WT as well as the retention of trafficking-deficient LQT2 mutants. The full text of this article is available online at http://www.circresaha.org.
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                Author and article information

                Journal
                J Transl Med
                J Transl Med
                Journal of Translational Medicine
                BioMed Central
                1479-5876
                2013
                23 February 2013
                : 11
                : 49
                Affiliations
                [1 ]Department of Electrophysiology, Heart Center Leipzig, Strümpellstr. 39, 04289, Leipzig, Germany
                [2 ]Department of Cardiology, Heart Center Leipzig, Strümpellstr. 39, 04289, Leipzig, Germany
                Article
                1479-5876-11-49
                10.1186/1479-5876-11-49
                3599085
                23432758
                d0324a3a-a8d5-42c0-ba08-3d20e1a76643
                Copyright ©2013 Kornej et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 23 August 2012
                : 20 February 2013
                Categories
                Research

                Medicine
                af recurrence,atrial fibrillation,autoantibodies,catheter ablation,heat shock proteins
                Medicine
                af recurrence, atrial fibrillation, autoantibodies, catheter ablation, heat shock proteins

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