Cardiac fibroblasts from rabbits with chronic aortic regurgitation incorporated more glucosamine into the extracellular matrix compared to controls (1.8:1 ratio, P=0.001).
In chronic aortic regurgitation, cardiac fibroblasts produce abnormal proportions of noncollagen ECM (specifically fibronectin) as a primary response to mechanical strain, which may contribute to heart failure pathogenesis.
Effect estimate: 1.8:1 ratio
p-value: p=0.001
BACKGROUND: Myocardial fibrosis is common in patients with chronic aortic regurgitation (AR). Experimentally, fibrosis with disproportionate noncollagen extracellular matrix (ECM) elements precedes and contributes to heart failure in AR. METHODS AND RESULTS: We assessed 3H-glucosamine and 3H-proline incorporation in ECM, variations in cardiac fibroblast (CF) gene expression, and synthesis of specific ECM proteins in CF cultured from rabbits with surgically induced chronic AR versus controls. To determine whether these variations are primary responses to AR, normal CF were exposed to mechanical strain that mimicked that of AR. Compared with normal CF, AR CF incorporated more glucosamine (1.8:1, P=0.001) into ECM, showed fibronectin gene upregulation (2.0:1, P=0.02), and synthesized more fibronectin (2:1 by Western blot, P<0.06; 1.5:1 by affinity chromatography, P=0.02). Proline incorporation was unchanged by AR (1.1:1, NS); collagen synthesis was unaffected (type I, 0.9:1; type III, 1.0:1, NS). Normal CF exposed to cyclical mechanical strain during culture showed parallel results: glucosamine incorporation increased with strain (2.1:1, P<0.001), proline incorporation was unaffected (1.1:1, NS), fibronectin gene expression (1.6:1, P=0.07) and fibronectin synthesis (Western analysis, 1.3:1, P<0.01; chromatography, 1.9:1, NS) were upregulated. CONCLUSIONS: In AR, CF produce abnormal proportions of noncollagen ECM, specifically fibronectin, with relatively little change in collagen synthesis. At least in part, this is a primary response to strain imposed on CF by AR. Further study must relate these findings to the pathogenesis of heart failure in AR.
Borer et al. (Tue,) conducted a other in Chronic aortic regurgitation. Surgically induced chronic aortic regurgitation and mechanical strain vs. Controls (normal cardiac fibroblasts without strain) was evaluated on Glucosamine incorporation into extracellular matrix (1.8:1 ratio, p=0.001). Cardiac fibroblasts from rabbits with chronic aortic regurgitation incorporated more glucosamine into the extracellular matrix compared to controls (1.8:1 ratio, P=0.001).