title: Characterization of the inflammatory and fibrotic response in a mouse model of cardiac pressure overload.
abstract: Myocardial fibrosis is an integral component of most cardiac pathologic conditions and contributes to the development of both systolic and diastolic dysfunction. Because of the availability of genetically manipulated animals, mouse models are essential for understanding the mechanisms involved in the pathogenesis of cardiac fibrosis. Accordingly, we characterized the inflammatory and fibrotic response in a mouse model of cardiac pressure overload due to transverse aortic constriction (TAC). Following TAC, mouse hearts exhibited induction of chemokines and proinflammatory cytokines, associated with macrophage, but not neutrophil, infiltration. Induction of inflammatory cytokines was followed by a late upregulation of transforming growth factor (TGF)-beta isoforms, activation of the Smad2/3 and Smad1/5 pathways, induction of matricellular proteins, and deposition of collagen. Inflammatory activity decreased after 28 days of TAC; at this timepoint established fibrosis was noted, accompanied by ventricular dilation and systolic dysfunction. Late induction of inhibitory mediators, such as TGF-beta, may play an essential role in the transition from inflammation to fibrosis by suppressing inflammatory gene synthesis while inducing matrix deposition. Our findings identify molecular mediators and pathways with a potential role in cardiac fibrosis laying the foundations for studies exploring the pathogenesis of fibrotic cardiac remodeling using genetically targeted mice.
authors.affiliation: Section of Cardiovascular Sciences, Department of Medicine, Baylor College of Medicine, One Baylor Plaza M/S BCM620, Houston, TX 77030, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xia
authors.forename: Keunsang
authors.initials: K
authors.lastname: Lee
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Daniel
authors.initials: D
authors.lastname: Corbett
authors.forename: Leonardo
authors.initials: L
authors.lastname: Mendoza
authors.forename: Nikolaos G
authors.initials: NG
authors.lastname: Frangogiannis
mesh_terms: D000818:Animals; D001011:Aorta / Q000601:surgery; D002339:Carotid Arteries / Q000601:surgery; D003094:Collagen / Q000378:metabolism*; D003326:Coronary Circulation / Q000502:physiology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D007150:Immunohistochemistry; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D009504:Neutrophils / Q000166:cytology / Q000276:immunology; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: D016207:Cytokines; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D003094:Collagen