Differential Behaviors of Atrial Versus Ventricular Fibroblasts

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 ␣-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-␤ 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 ␣-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-␤ 1 -stimulated atrial-ventricular fibroblast proliferative response differences. Conclusions-Atrial

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“…Although it has been reported that the atrium is more susceptible to fibrotic changes than the ventricle, 16 the precise mechanisms are still unknown. It has been shown that the plasma level of NOx, an NO metabolite, was significantly decreased in AF patients 17 and that AF was associated with a marked decrease in eNOS protein expression.…”

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“…A particularly important component is atrial fibrosis, which in experimental models occurs earlier in the course of CHF, and to a much greater extent, than in the ventricles, at least in part because of atrial-ventricular fibroblastphenotype differences. 4 Congestive heart failure-related fibrosis slowly, if at all, and the AFpromoting substrate predominantly tracks fibrosis rather than other components of atrial remodelling like ion-current or connexin changes. Unlike the case for AF-induced remodelling, the atrial ion-current changes in CHF do not abbreviate APD or cause overall conduction slowing, 113,114 so they do not contribute directly to arrhythmogenesis.…”

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“…TGF-β 1 , secreted by both fibroblasts and cardiomyocytes, is an important profibrotic mediator (119). Cardiac overexpression of constitutively active TGF-β 1 causes selective atrial fibrosis, conduction heterogeneity, and AF susceptibility (120).…”

“…Cardiac overexpression of constitutively active TGF-β 1 causes selective atrial fibrosis, conduction heterogeneity, and AF susceptibility (120). TGF-β 1 functions as a downstream mediator of Ang II in both paracrine and autocrine ways (119). It acts primarily through the SMAD pathway to stimu-…”