title: PKA phosphorylation of the small heat-shock protein Hsp20 enhances its cardioprotective effects.
abstract: The small heat-shock protein Hsp20 (heat-shock protein 20), also known as HspB6, has been shown to protect against a number of pathophysiological cardiac processes, including hypertrophy and apoptosis. Following β-adrenergic stimulation and local increases in cAMP, Hsp20 is phosphorylated on Ser16 by PKA (protein kinase A). This covalent modification is required for many of its cardioprotective effects. Both Hsp20 expression levels and its phosphorylation on Ser16 are increased in ischaemic myocardium. Transgenic mouse models with cardiac-specific overexpression of Hsp20 that are subject to ischaemia/reperfusion show smaller myocardial infarcts, and improved recovery of contractile performance during the reperfusion phase, compared with wild-type mice. This has been attributed to Hsp20's ability to protect against cardiomyocyte necrosis and apoptosis. Phosphomimics of Hsp20 (S16D mutants) confer improved protection from β-agonist-induced apoptosis in the heart, whereas phospho-null mutants (S16A) provide no protection. Naturally occurring mutants of Hsp20 at position 20 (P20L substitution) are associated with markedly reduced Hsp20 phosphorylation at Ser16, and this lack of phosphorylation correlates with abrogation of Hsp20's cardioprotective effects. Therefore phosphorylation of Hsp20 at Ser16 by PKA is vital for the cardioprotective actions of this small heat-shock protein. Selective targeting of signalling elements that can enhance this modification represents an exciting new therapeutic avenue for the prevention and treatment of myocardial remodelling and ischaemic injury.
authors.affiliation: Centre for Molecular Pharmacology, College of Medical, Veterinary and Life Sciences, University of Glasgow, University Avenue, Glasgow G12 8QQ, UK. h.edwards.1@research.gla.ac.uk
authors.forename: Helen V
authors.initials: HV
authors.lastname: Edwards
authors.forename: John D
authors.initials: JD
authors.lastname: Scott
authors.forename: George S
authors.initials: GS
authors.lastname: Baillie
mesh_terms: D000818:Animals; D017209:Apoptosis; D006332:Cardiomegaly / Q000201:enzymology / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D050886:HSP20 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism*; D006321:Heart / Q000503:physiopathology; D006801:Humans; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000502:physiology; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D050886:HSP20 Heat-Shock Proteins; D011943:Receptors, Adrenergic, beta; D017868:Cyclic AMP-Dependent Protein Kinases