Mimicking phosphorylation of alphaB-crystallin on serine-59 is necessary and sufficient to provide maximal protection of cardiac myocytes from apoptosis

AlphaB-crystallin (alphaBC), a small heat shock protein expressed in high levels in the heart, is phosphorylated on Ser-19, 45, and 59 after stress. However, it is not known whether alphaBC phosphorylation directly affects cell survival. In the present study, constructs were prepared that encode for...

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Veröffentlicht in:Circulation research 2003-02, Vol.92 (2), p.203
Hauptverfasser: Morrison, Lisa E, Hoover, Holly E, Thuerauf, Donna J, Glembotski, Christopher C
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container_title Circulation research
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creator Morrison, Lisa E
Hoover, Holly E
Thuerauf, Donna J
Glembotski, Christopher C
description AlphaB-crystallin (alphaBC), a small heat shock protein expressed in high levels in the heart, is phosphorylated on Ser-19, 45, and 59 after stress. However, it is not known whether alphaBC phosphorylation directly affects cell survival. In the present study, constructs were prepared that encode forms of alphaBC harboring Ser to Ala (blocks phosphorylation) or Ser to Glu (mimics phosphorylation) mutations at positions 19, 45, and 59. The effects of each form on apoptosis of cultured cardiac myocytes after hyperosmotic or hypoxic stress were assessed. Compared with controls, cells that expressed alphaBC with Ser to Ala substitutions at all three positions, alphaBC(AAA), exhibited more stress-induced apoptosis. Cells expressing either alphaBC(AAE) or (EEE) exhibited 3-fold less apoptosis than cells expressing alphaBC(AAA), indicating that phosphorylation of Ser-59 confers protection. alphaBC is known to bind to procaspase-3 and to decrease caspase-3 activation. Compared with cells expressing alphaBC(AAA), the activation of caspase-3 was decreased by 3-fold in cells expressing alphaBC(AAE). These results demonstrate that mimicking the phosphorylation of alphaBC on Ser-59 is necessary and sufficient to confer caspase-3 inhibition and protection of cardiac myocytes against hyperosmotic or hypoxic stress. These findings provide direct evidence that alphaBC(S59P) contributes to the cardioprotection observed after physiologically relevant stresses, such as transient hypoxia. Identifying the targets of alphaBC(S59P) will reveal important details about the mechanism underlying the cytoprotective effects of this small heat shock protein.
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However, it is not known whether alphaBC phosphorylation directly affects cell survival. In the present study, constructs were prepared that encode forms of alphaBC harboring Ser to Ala (blocks phosphorylation) or Ser to Glu (mimics phosphorylation) mutations at positions 19, 45, and 59. The effects of each form on apoptosis of cultured cardiac myocytes after hyperosmotic or hypoxic stress were assessed. Compared with controls, cells that expressed alphaBC with Ser to Ala substitutions at all three positions, alphaBC(AAA), exhibited more stress-induced apoptosis. Cells expressing either alphaBC(AAE) or (EEE) exhibited 3-fold less apoptosis than cells expressing alphaBC(AAA), indicating that phosphorylation of Ser-59 confers protection. alphaBC is known to bind to procaspase-3 and to decrease caspase-3 activation. Compared with cells expressing alphaBC(AAA), the activation of caspase-3 was decreased by 3-fold in cells expressing alphaBC(AAE). These results demonstrate that mimicking the phosphorylation of alphaBC on Ser-59 is necessary and sufficient to confer caspase-3 inhibition and protection of cardiac myocytes against hyperosmotic or hypoxic stress. These findings provide direct evidence that alphaBC(S59P) contributes to the cardioprotection observed after physiologically relevant stresses, such as transient hypoxia. 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However, it is not known whether alphaBC phosphorylation directly affects cell survival. In the present study, constructs were prepared that encode forms of alphaBC harboring Ser to Ala (blocks phosphorylation) or Ser to Glu (mimics phosphorylation) mutations at positions 19, 45, and 59. The effects of each form on apoptosis of cultured cardiac myocytes after hyperosmotic or hypoxic stress were assessed. Compared with controls, cells that expressed alphaBC with Ser to Ala substitutions at all three positions, alphaBC(AAA), exhibited more stress-induced apoptosis. Cells expressing either alphaBC(AAE) or (EEE) exhibited 3-fold less apoptosis than cells expressing alphaBC(AAA), indicating that phosphorylation of Ser-59 confers protection. alphaBC is known to bind to procaspase-3 and to decrease caspase-3 activation. Compared with cells expressing alphaBC(AAA), the activation of caspase-3 was decreased by 3-fold in cells expressing alphaBC(AAE). 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These results demonstrate that mimicking the phosphorylation of alphaBC on Ser-59 is necessary and sufficient to confer caspase-3 inhibition and protection of cardiac myocytes against hyperosmotic or hypoxic stress. These findings provide direct evidence that alphaBC(S59P) contributes to the cardioprotection observed after physiologically relevant stresses, such as transient hypoxia. Identifying the targets of alphaBC(S59P) will reveal important details about the mechanism underlying the cytoprotective effects of this small heat shock protein.</abstract><cop>United States</cop><pub>Lippincott Williams &amp; Wilkins Ovid Technologies</pub><pmid>12574148</pmid></addata></record>
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subjects alpha-Crystallin B Chain - biosynthesis
alpha-Crystallin B Chain - genetics
Amino Acid Substitution
Animals
Apoptosis - drug effects
Apoptosis - physiology
Base Sequence
Caspase 3
Caspases - metabolism
Cell Hypoxia - physiology
Cell Survival
Cells, Cultured
In Situ Nick-End Labeling
Molecular Mimicry - genetics
Molecular Sequence Data
Mutagenesis, Site-Directed
Myocytes, Cardiac - cytology
Myocytes, Cardiac - drug effects
Myocytes, Cardiac - metabolism
Osmolar Concentration
Phosphorylation
Rats
Rats, Sprague-Dawley
Sorbitol - pharmacology
Structure-Activity Relationship
Transfection
title Mimicking phosphorylation of alphaB-crystallin on serine-59 is necessary and sufficient to provide maximal protection of cardiac myocytes from apoptosis
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