This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 117/13/1630    most recent CIRCULATIONAHA.107.748053v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Google Scholar Articles by Burstein, B. Articles by Nattel, S. PubMed PubMed Citation Articles by Burstein, B. Articles by Nattel, S. Related Collections Structure Animal models of human disease Arrythmias-basic studies Related Article

(Circulation. 2008;117:1630-1641.)
© 2008 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Differential Behaviors of Atrial Versus Ventricular Fibroblasts

A Potential Role for Platelet-Derived Growth Factor in Atrial-Ventricular Remodeling Differences

Brett Burstein, BSc; Eric Libby, BSc; Angelino Calderone, PhD; Stanley Nattel, MD

From the Departments of Medicine (B.B., S.N.) and Physiology (A.C.), Montreal Heart Institute and Université de Montréal, and Departments of Pharmacology and Therapeutics (B.B., S.N.) and Physiology (E.L.), McGill University, Montreal, Quebec, Canada.

Correspondence to Stanley Nattel, 5000 Belanger St E, Montreal, H1T 1C8, Quebec, Canada. E-mail stanley.nattel{at}icm-mhi.org

Received April 26, 2007; accepted February 5, 2008.

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 -smooth muscle actin expression than ventricular fibroblasts. Atrial fibroblast proliferation ([³H]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-β₁. 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 -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-β₁–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.

---

 

CLINICAL PERSPECTIVE

Related Article:

Clinical Summaries
Circulation 2008 117: 1621. [Full Text]

This article has been cited by other articles:

				S. Nattel, B. Burstein, and D. Dobrev Atrial Remodeling and Atrial Fibrillation: Mechanisms and Implications Circ Arrhythmia Electrophysiol, April 1, 2008; 1(1): 62 - 73. [Full Text] [PDF]