title: Long-Term Overexpression of Hsp70 Does Not Protect against Cardiac Dysfunction and Adverse Remodeling in a MURC Transgenic Mouse Model with Chronic Heart Failure and Atrial Fibrillation.
abstract: Previous animal studies had shown that increasing heat shock protein 70 (Hsp70) using a transgenic, gene therapy or pharmacological approach provided cardiac protection in models of acute cardiac stress. Furthermore, clinical studies had reported associations between Hsp70 levels and protection against atrial fibrillation (AF). AF is the most common cardiac arrhythmia presenting in cardiology clinics and is associated with increased rates of heart failure and stroke. Improved therapies for AF and heart failure are urgently required. Despite promising observations in animal studies which targeted Hsp70, we recently reported that increasing Hsp70 was unable to attenuate cardiac dysfunction and pathology in a mouse model which develops heart failure and intermittent AF. Given our somewhat unexpected finding and the extensive literature suggesting Hsp70 provides cardiac protection, it was considered important to assess whether Hsp70 could provide protection in another mouse model of heart failure and AF. The aim of the current study was to determine whether increasing Hsp70 could attenuate adverse cardiac remodeling, cardiac dysfunction and episodes of arrhythmia in a mouse model of heart failure and AF due to overexpression of Muscle-Restricted Coiled-Coil (MURC). Cardiac function and pathology were assessed in mice at approximately 12 months of age. We report here, that chronic overexpression of Hsp70 was unable to provide protection against cardiac dysfunction, conduction abnormalities, fibrosis or characteristic molecular markers of the failing heart. In summary, elevated Hsp70 may provide protection in acute cardiac stress settings, but appears insufficient to protect the heart under chronic cardiac disease conditions.
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, 3004, Australia.
authors.forename: Bianca C
authors.initials: BC
authors.lastname: Bernardo
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, 3004, Australia.
authors.forename: Geeta
authors.initials: G
authors.lastname: Sapra
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, 3004, Australia.
authors.forename: Natalie L
authors.initials: NL
authors.lastname: Patterson
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, 3004, Australia.
authors.forename: Nelly
authors.initials: N
authors.lastname: Cemerlang
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, 3004, Australia.
authors.forename: Helen
authors.initials: H
authors.lastname: Kiriazis
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ueyama
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, 3004, Australia.|Garvan Institute of Medical Research, Darlinghurst, 2010, Australia.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Febbraio
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, 3004, Australia.
authors.forename: Julie R
authors.initials: JR
authors.lastname: McMullen
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism / Q000503:physiopathology*; D002908:Chronic Disease; D024042:Collagen Type I / Q000378:metabolism; D004195:Disease Models, Animal; D004562:Electrocardiography; D005260:Female; D005355:Fibrosis; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology*; D006352:Heart Ventricles / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000235:genetics; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D020257:Ventricular Remodeling; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
chemical_list: C532667:Cavin4 protein, mouse; D024042:Collagen Type I; D018840:HSP70 Heat-Shock Proteins; D009124:Muscle Proteins; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein