Myofibroblast Phenotype and Reversibility of Fibrosis in Patients With End-Stage Heart Failure
| Autor: | Emma L. Robinson, Johan Van Cleemput, Filip Rega, Ronald B. Driesen, Guillaume Gilbert, Chandan K. Nagaraju, Sander Trenson, Stefan Janssens, Karin R. Sipido, H. Llewelyn Roderick, Mouna Abdesselem, Eef Dries, Bart Meyns |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Pathology
Cell Adhesion Molecules/analysis Heart Failure/metabolism Myocardium/metabolism Myofibroblasts/metabolism 030204 cardiovascular system & hematology Protein-Lysine 6-Oxidase Extracellular matrix 0302 clinical medicine Fibrosis contractile function Ventricular Dysfunction Medicine 030212 general & internal medicine Osteopontin Myofibroblasts Cells Cultured Fibroblasts/metabolism Cultured biology Cell Differentiation Immunohistochemistry 3. Good health Disease Progression medicine.symptom Cardiology and Cardiovascular Medicine Myofibroblast Signal Transduction medicine.medical_specialty FIBROBLASTS Cells extracellular matrix INHIBITION Lysyl oxidase Inflammation Periostin Transforming Growth Factor beta1 03 medical and health sciences fibroblasts Osteopontin/analysis Humans CARDIAC FIBROSIS Heart Failure business.industry GROWTH-FACTOR-BETA Myocardium medicine.disease DYSFUNCTION Protein-Lysine 6-Oxidase/analysis HYPERTROPHY Transforming Growth Factor beta1/analysis Ventricular Dysfunction/etiology MYOCARDIAL-INFARCTION inflammation biology.protein business Cell Adhesion Molecules Transforming growth factor |
| Zdroj: | Journal of the American College of Cardiology Journal of the American College of Cardiology, 73(18), 2267-2282. Elsevier Science |
| ISSN: | 0735-1097 |
| Popis: | BACKGROUND: Interstitial fibrosis is an important component of diastolic, and systolic, dysfunction in heart failure (HF) and depends on activation and differentiation of fibroblasts into myofibroblasts (MyoFb). Recent clinical evidence suggests that in late-stage HF, fibrosis is not reversible. OBJECTIVES: The study aims to examine the degree of differentiation of cardiac MyoFb in end-stage HF and the potential for their phenotypic reversibility. METHODS: Fibroblasts were isolated from the left ventricle of the explanted hearts of transplant recipients (ischemic and dilated cardiomyopathy), and from nonused donor hearts. Fibroblasts were maintained in culture without passaging for 4 or 8 days (treatment studies). Phenotyping included functional testing, immunostaining, and expression studies for markers of differentiation. These data were complemented with immunohistology and expression studies in tissue samples. RESULTS: Interstitial fibrosis with cross-linked collagen is prominent in HF hearts, with presence of activated MyoFbs. Tissue levels of transforming growth factor (TGF)-β1, lysyl oxidase, periostin, and osteopontin are elevated. Fibroblastic cells isolated from HF hearts are predominantly MyoFb, proliferative or nonproliferative, with mature α-smooth muscle actin stress fibers. HF MyoFb express high levels of profibrotic cytokines and the TGF-β1 pathway is activated. Inhibition of TGF-β1 receptor kinase in HF MyoFb promotes dedifferentiation of MyoFb with loss of α-smooth muscle actin and depolymerization of stress fibers, and reduces the expression of profibrotic genes and cytokines levels to non-HF levels. CONCLUSION: MyoFb in end-stage HF have a variable degree of differentiation and retain the capacity to return to a less activated state, validating the potential for developing antifibrotic therapy targeting MyoFb. ispartof: JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY vol:73 issue:18 pages:2267-2282 ispartof: location:United States status: published |
| Databáze: | OpenAIRE |
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