title: Small heat-shock protein Hsp20 attenuates beta-agonist-mediated cardiac remodeling through apoptosis signal-regulating kinase 1.
abstract: Chronic stimulation of the beta-adrenergic neurohormonal axis contributes to the progression of heart failure and mortality in animal models and human patients. In cardiomyocytes, activation of the beta-adrenergic pathway has been shown to result in transiently increased expression of a cardiac small heat-shock protein Hsp20. The present study shows that cardiac overexpression (10-fold) of Hsp20 may protect the heart against beta-agonist-induced cardiac remodeling, associated with isoproterenol (50 mug/g per day) infusion for 14 days. Hsp20 attenuated the cardiac hypertrophic response, markedly reduced interstitial fibrosis, and decreased apoptosis. Contractility was also preserved in hearts with increased Hsp20 levels. These beneficial effects were associated with attenuation of the ASK1-JNK/p38 (apoptosis signal-regulating kinase 1/c-Jun NH(2)-terminal kinase/p38) signaling cascade triggered by isoproterenol, whereas there was no difference in either extracellular signal-related kinase 1/2 or Akt activation. Parallel in vitro experiments supported the inhibitory role of Hsp20 on enforced ASK1-JNK/p38 activation in both H9c2 cells and adult rat cardiomyocytes. Immunostaining studies also demonstrated that Hsp20 colocalizes with ASK1 in cardiomyocytes. Taken together, our findings indicate that (1) beta-agonist-induced cardiac injury is associated with activation of the ASK1-JNK/p38 cascade; (2) increased expression of Hsp20 attenuates the induction of remodeling, dysfunction, and apoptosis in response to sustained beta-adrenergic stimulation; and (3) the beneficial effects of Hsp20 are at least partially attributable to inhibition of the ASK1-signaling cascade.
authors.affiliation: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Ohio 45267-0575, USA.
authors.forename: Guo-Chang
authors.initials: GC
authors.lastname: Fan
authors.forename: Qunying
authors.initials: Q
authors.lastname: Yuan
authors.forename: Guojie
authors.initials: G
authors.lastname: Song
authors.forename: Yigang
authors.initials: Y
authors.lastname: Wang
authors.forename: Guoli
authors.initials: G
authors.lastname: Chen
authors.forename: Jiang
authors.initials: J
authors.lastname: Qian
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Zhou
authors.forename: Yong J
authors.initials: YJ
authors.lastname: Lee
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ashraf
authors.forename: Evangelia G
authors.initials: EG
authors.lastname: Kranias
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006332:Cardiomegaly / Q000139:chemically induced / Q000473:pathology; D002316:Cardiotonic Agents / Q000378:metabolism / Q000494:pharmacology*; D002478:Cells, Cultured; D015536:Down-Regulation; D004789:Enzyme Activation / Q000187:drug effects; D005355:Fibrosis; D050886:HSP20 Heat-Shock Proteins / Q000378:metabolism / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D007545:Isoproterenol / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000037:antagonists & inhibitors*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D010770:Phosphotransferases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013312:Stress, Physiological / Q000201:enzymology; D020257:Ventricular Remodeling / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000318:Adrenergic beta-Agonists; D002316:Cardiotonic Agents; D050886:HSP20 Heat-Shock Proteins; D010770:Phosphotransferases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D007545:Isoproterenol