Differential Behaviors of Atrial Versus Ventricular Fibroblasts
- 1 April 2008
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation
- Vol. 117 (13), 1630-1641
- https://doi.org/10.1161/circulationaha.107.748053
Abstract
Background— In various heart disease paradigms, atria show stronger fibrotic responses than ventricles. The possibility that atrial and ventricular fibroblasts respond differentially to pathological stimuli has not been examined. Methods and Results— We compared various morphological, secretory, and proliferative response indexes of canine atrial versus ventricular fibroblasts. Cultured atrial fibroblasts showed faster cell surface area increases, distinct morphology at confluence, and greater α-smooth muscle actin expression than ventricular fibroblasts. Atrial fibroblast proliferation ([ 3 H]thymidine incorporation) responses were consistently greater for a range of growth factors, including fetal bovine serum, platelet-derived growth factor (PDGF), basic fibroblast growth factor, angiotensin II, endothelin-1, and transforming growth factor-β 1 . Normal atrial tissue showed larger myofibroblast density compared with ventricular tissue, and the difference was exaggerated by congestive heart failure. Congestive heart failure atria showed larger fractions of fibroblasts in mitotic phases compared with ventricles and displayed enhanced gene expression of fibroblast-selective markers (collagen-1, collagen-3, fibronectin-1). Gene microarrays revealed 225 differentially expressed transcript probe sets between paired atrial and ventricular fibroblast samples, including extracellular matrix (eg, fibronectin, laminin, fibulin), cell signaling (PDGF, PDGF receptor, angiopoietin, vascular endothelial growth factor), structure (keratin), and metabolism (xanthine dehydrogenase) genes, identifying PDGF as a candidate contributor to atrial-ventricular fibroblast differences. PDGF receptor gene expression was greater in normal atrium compared with ventricle, and congestive heart failure differentially enhanced atrial versus ventricular PDGF and PDGF receptor gene expression. PDGF receptor protein expression and α-smooth muscle actin protein expression were enhanced in isolated congestive heart failure fibroblasts. The PDGF receptor tyrosine kinase inhibitor AG1295 eliminated fetal bovine serum– and transforming growth factor-β 1 –stimulated atrial-ventricular fibroblast proliferative response differences. Conclusions— Atrial fibroblasts behave differently than ventricular fibroblasts over a range of in vitro and in vivo paradigms, with atrial fibroblasts showing enhanced reactivity that may explain greater atrial fibrotic responses. PDGF signaling is particularly important for atrium-selective fibroblast responses and may represent a novel target for arrhythmogenic atrial structural remodeling prevention.Keywords
This publication has 42 references indexed in Scilit:
- Innovative approaches to anti-arrhythmic drug therapyNature Reviews Drug Discovery, 2006
- Platelet-Derived Growth Factor D Induces Cardiac Fibrosis and Proliferation of Vascular Smooth Muscle Cells in Heart-Specific Transgenic MiceCirculation Research, 2005
- Intracardiac fibroblasts, but not bone marrow derived cells, are the origin of myofibroblasts in myocardial infarct repairCardiovascular Pathology, 2005
- Comparison of ion channel distribution and expression in cardiomyocytes of canine pulmonary veins versus left atriumCardiovascular Research, 2005
- Nestin‐expressing neural stem cells identified in the scar following myocardial infarctionJournal of Cellular Physiology, 2004
- Mice with Cardiac-Restricted Angiotensin-Converting Enzyme (ACE) Have Atrial Enlargement, Cardiac Arrhythmia, and Sudden DeathThe American Journal of Pathology, 2004
- Differences in atrial versus ventricular remodeling in dogs with ventricular tachypacing-induced congestive heart failureCardiovascular Research, 2004
- Cardiac remodeling and atrial fibrillation in transgenic miceoverexpressing junctinThe FASEB Journal, 2002
- Is angiotensin II a proliferative factor of cardiac fibroblasts?Cardiovascular Research, 2002
- Rat Fibroblasts Cultured from Various Organs Exhibit Differences in α-Smooth Muscle Actin Expression, Cytoskeletal Pattern, and Adhesive Structure OrganizationExperimental Cell Research, 1998