title: Myofibroblast-mediated mechanisms of pathological remodelling of the heart.
abstract: The syncytium of cardiomyocytes in the heart is tethered within a matrix composed principally of type I fibrillar collagen. The matrix has diverse mechanical functions that ensure the optimal contractile efficiency of this muscular pump. In the diseased heart, cardiomyocytes are lost to necrotic cell death, and phenotypically transformed fibroblast-like cells-termed 'myofibroblasts'-are activated to initiate a 'reparative' fibrosis. The structural integrity of the myocardium is preserved by this scar tissue, although at the expense of its remodelled architecture, which has increased tissue stiffness and propensity to arrhythmias. A persisting population of activated myofibroblasts turns this fibrous tissue into a living 'secretome' that generates angiotensin II and its type 1 receptor, and fibrogenic growth factors (such as transforming growth factor-β), all of which collectively act as a signal-transducer-effector signalling pathway to type I collagen synthesis and, therefore, fibrosis. Persistent myofibroblasts, and the resultant fibrous tissue they produce, cause progressive adverse myocardial remodelling, a pathological hallmark of the failing heart irrespective of its etiologic origin. Herein, we review relevant cellular, subcellular, and molecular mechanisms integral to cardiac fibrosis and consequent remodelling of atria and ventricles with a heterogeneity in cardiomyocyte size. Signalling pathways that antagonize collagen fibrillogenesis provide novel strategies for cardioprotection.
authors.affiliation: Division of Cardiovascular Diseases, University of Tennessee Health Science Center, 956 Court Avenue, Memphis, TN 38163, USA. KTWeber@uthsc.edu
authors.forename: Karl T
authors.initials: KT
authors.lastname: Weber
authors.forename: Yao
authors.initials: Y
authors.lastname: Sun
authors.forename: Syamal K
authors.initials: SK
authors.lastname: Bhattacharya
authors.forename: Robert A
authors.initials: RA
authors.lastname: Ahokas
authors.forename: Ivan C
authors.initials: IC
authors.lastname: Gerling
mesh_terms: D000818:Animals; D016923:Cell Death; D003094:Collagen / Q000187:drug effects / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D006331:Heart Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009336:Necrosis; D010641:Phenotype; D015398:Signal Transduction; D020257:Ventricular Remodeling
chemical_list: D003094:Collagen