Induction of heat shock response protects the heart against atrial fibrillation

Bianca J J M Brundel, Akiko Shiroshita-Takeshita, Xiaoyan Qi, Yung-Hsin Yeh, Denis Chartier, Isabelle C van Gelder, Robert H Henning, Harm H Kampinga, Stanley Nattel

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

There is evidence suggesting that heat shock proteins (HSPs) may protect against clinical atrial fibrillation (AF). We evaluated the effect of HSP induction in an in vitro atrial cell line (HL-1) model of tachycardia remodeling and in tachypaced isolated canine atrial cardiomyocytes. We also evaluated the effect of HSP induction on in vivo AF promotion by atrial tachycardia-induced remodeling in dogs. Tachypacing (3 Hz) significantly and progressively reduced Ca(2+) transients and cell shortening of HL-1 myocytes over 4 hours. These reductions were prevented by HSP-inducing pretreatments: mild heat shock, geranylgeranylacetone (GGA), and transfection with human HSP27 or the phosphorylation-mimicking HSP27-DDD. However, treatment with HSP70 or the phosphorylation-deficient mutant HSP27-AAA failed to alter tachycardia-induced Ca(2+) transient and cell-shortening reductions, and downregulation (short interfering RNA) of HSP27 prevented GGA-mediated protection. Tachypacing (3 Hz) for 24 hours in vitro significantly reduced L-type Ca(2+) current and action potential duration in canine atrial cardiomyocytes; these effects were prevented when tachypacing was performed in cells exposed to GGA. In vivo treatment with GGA increased HSP expression and suppressed refractoriness abbreviation and AF promotion in dogs subjected to 1-week atrial tachycardia-induced remodeling. In conclusion, our findings indicate that (1) HSP induction protects against atrial tachycardia-induced remodeling, (2) the protective effect in HL-1 myocytes requires HSP27 induction and phosphorylation, and (3) the orally administered HSP inducer GGA protects against AF in a clinically relevant animal model. These findings advance our understanding of the biochemical determinants of AF and suggest the possibility that HSP induction may be an interesting novel approach to preventing clinical AF.

Original languageEnglish
Pages (from-to)1394-402
Number of pages9
JournalCirculation Research
Volume99
Issue number12
DOIs
Publication statusPublished - 8 Dec 2006

Cite this

Brundel, B. J. J. M., Shiroshita-Takeshita, A., Qi, X., Yeh, Y-H., Chartier, D., van Gelder, I. C., ... Nattel, S. (2006). Induction of heat shock response protects the heart against atrial fibrillation. Circulation Research, 99(12), 1394-402. https://doi.org/10.1161/01.RES.0000252323.83137.fe
Brundel, Bianca J J M ; Shiroshita-Takeshita, Akiko ; Qi, Xiaoyan ; Yeh, Yung-Hsin ; Chartier, Denis ; van Gelder, Isabelle C ; Henning, Robert H ; Kampinga, Harm H ; Nattel, Stanley. / Induction of heat shock response protects the heart against atrial fibrillation. In: Circulation Research. 2006 ; Vol. 99, No. 12. pp. 1394-402.
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abstract = "There is evidence suggesting that heat shock proteins (HSPs) may protect against clinical atrial fibrillation (AF). We evaluated the effect of HSP induction in an in vitro atrial cell line (HL-1) model of tachycardia remodeling and in tachypaced isolated canine atrial cardiomyocytes. We also evaluated the effect of HSP induction on in vivo AF promotion by atrial tachycardia-induced remodeling in dogs. Tachypacing (3 Hz) significantly and progressively reduced Ca(2+) transients and cell shortening of HL-1 myocytes over 4 hours. These reductions were prevented by HSP-inducing pretreatments: mild heat shock, geranylgeranylacetone (GGA), and transfection with human HSP27 or the phosphorylation-mimicking HSP27-DDD. However, treatment with HSP70 or the phosphorylation-deficient mutant HSP27-AAA failed to alter tachycardia-induced Ca(2+) transient and cell-shortening reductions, and downregulation (short interfering RNA) of HSP27 prevented GGA-mediated protection. Tachypacing (3 Hz) for 24 hours in vitro significantly reduced L-type Ca(2+) current and action potential duration in canine atrial cardiomyocytes; these effects were prevented when tachypacing was performed in cells exposed to GGA. In vivo treatment with GGA increased HSP expression and suppressed refractoriness abbreviation and AF promotion in dogs subjected to 1-week atrial tachycardia-induced remodeling. In conclusion, our findings indicate that (1) HSP induction protects against atrial tachycardia-induced remodeling, (2) the protective effect in HL-1 myocytes requires HSP27 induction and phosphorylation, and (3) the orally administered HSP inducer GGA protects against AF in a clinically relevant animal model. These findings advance our understanding of the biochemical determinants of AF and suggest the possibility that HSP induction may be an interesting novel approach to preventing clinical AF.",
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Brundel, BJJM, Shiroshita-Takeshita, A, Qi, X, Yeh, Y-H, Chartier, D, van Gelder, IC, Henning, RH, Kampinga, HH & Nattel, S 2006, 'Induction of heat shock response protects the heart against atrial fibrillation' Circulation Research, vol. 99, no. 12, pp. 1394-402. https://doi.org/10.1161/01.RES.0000252323.83137.fe

Induction of heat shock response protects the heart against atrial fibrillation. / Brundel, Bianca J J M; Shiroshita-Takeshita, Akiko; Qi, Xiaoyan; Yeh, Yung-Hsin; Chartier, Denis; van Gelder, Isabelle C; Henning, Robert H; Kampinga, Harm H; Nattel, Stanley.

In: Circulation Research, Vol. 99, No. 12, 08.12.2006, p. 1394-402.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Induction of heat shock response protects the heart against atrial fibrillation

AU - Brundel, Bianca J J M

AU - Shiroshita-Takeshita, Akiko

AU - Qi, Xiaoyan

AU - Yeh, Yung-Hsin

AU - Chartier, Denis

AU - van Gelder, Isabelle C

AU - Henning, Robert H

AU - Kampinga, Harm H

AU - Nattel, Stanley

PY - 2006/12/8

Y1 - 2006/12/8

N2 - There is evidence suggesting that heat shock proteins (HSPs) may protect against clinical atrial fibrillation (AF). We evaluated the effect of HSP induction in an in vitro atrial cell line (HL-1) model of tachycardia remodeling and in tachypaced isolated canine atrial cardiomyocytes. We also evaluated the effect of HSP induction on in vivo AF promotion by atrial tachycardia-induced remodeling in dogs. Tachypacing (3 Hz) significantly and progressively reduced Ca(2+) transients and cell shortening of HL-1 myocytes over 4 hours. These reductions were prevented by HSP-inducing pretreatments: mild heat shock, geranylgeranylacetone (GGA), and transfection with human HSP27 or the phosphorylation-mimicking HSP27-DDD. However, treatment with HSP70 or the phosphorylation-deficient mutant HSP27-AAA failed to alter tachycardia-induced Ca(2+) transient and cell-shortening reductions, and downregulation (short interfering RNA) of HSP27 prevented GGA-mediated protection. Tachypacing (3 Hz) for 24 hours in vitro significantly reduced L-type Ca(2+) current and action potential duration in canine atrial cardiomyocytes; these effects were prevented when tachypacing was performed in cells exposed to GGA. In vivo treatment with GGA increased HSP expression and suppressed refractoriness abbreviation and AF promotion in dogs subjected to 1-week atrial tachycardia-induced remodeling. In conclusion, our findings indicate that (1) HSP induction protects against atrial tachycardia-induced remodeling, (2) the protective effect in HL-1 myocytes requires HSP27 induction and phosphorylation, and (3) the orally administered HSP inducer GGA protects against AF in a clinically relevant animal model. These findings advance our understanding of the biochemical determinants of AF and suggest the possibility that HSP induction may be an interesting novel approach to preventing clinical AF.

AB - There is evidence suggesting that heat shock proteins (HSPs) may protect against clinical atrial fibrillation (AF). We evaluated the effect of HSP induction in an in vitro atrial cell line (HL-1) model of tachycardia remodeling and in tachypaced isolated canine atrial cardiomyocytes. We also evaluated the effect of HSP induction on in vivo AF promotion by atrial tachycardia-induced remodeling in dogs. Tachypacing (3 Hz) significantly and progressively reduced Ca(2+) transients and cell shortening of HL-1 myocytes over 4 hours. These reductions were prevented by HSP-inducing pretreatments: mild heat shock, geranylgeranylacetone (GGA), and transfection with human HSP27 or the phosphorylation-mimicking HSP27-DDD. However, treatment with HSP70 or the phosphorylation-deficient mutant HSP27-AAA failed to alter tachycardia-induced Ca(2+) transient and cell-shortening reductions, and downregulation (short interfering RNA) of HSP27 prevented GGA-mediated protection. Tachypacing (3 Hz) for 24 hours in vitro significantly reduced L-type Ca(2+) current and action potential duration in canine atrial cardiomyocytes; these effects were prevented when tachypacing was performed in cells exposed to GGA. In vivo treatment with GGA increased HSP expression and suppressed refractoriness abbreviation and AF promotion in dogs subjected to 1-week atrial tachycardia-induced remodeling. In conclusion, our findings indicate that (1) HSP induction protects against atrial tachycardia-induced remodeling, (2) the protective effect in HL-1 myocytes requires HSP27 induction and phosphorylation, and (3) the orally administered HSP inducer GGA protects against AF in a clinically relevant animal model. These findings advance our understanding of the biochemical determinants of AF and suggest the possibility that HSP induction may be an interesting novel approach to preventing clinical AF.

KW - Animals

KW - Atrial Fibrillation/metabolism

KW - Cardiotonic Agents/pharmacology

KW - Diterpenes/pharmacology

KW - Dogs

KW - HSP27 Heat-Shock Proteins

KW - HSP70 Heat-Shock Proteins/genetics

KW - Heart Atria/cytology

KW - Heat-Shock Proteins/genetics

KW - Heat-Shock Response/drug effects

KW - Humans

KW - Myocardial Contraction/drug effects

KW - Myocytes, Cardiac/cytology

KW - Neoplasm Proteins/genetics

KW - Pacemaker, Artificial

KW - Patch-Clamp Techniques

KW - Phosphorylation

KW - RNA, Small Interfering

KW - Transfection

U2 - 10.1161/01.RES.0000252323.83137.fe

DO - 10.1161/01.RES.0000252323.83137.fe

M3 - Article

VL - 99

SP - 1394

EP - 1402

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

IS - 12

ER -