Vesnarinone-mediated alterations of gene expression in cardiac fibroblasts from aortic regurgitant hearts

American Journal of Therapeutics
Sharada TruterJeffrey S Borer

Abstract

Pathologic fibrosis precedes heart failure (CHF) and death in experimental aortic regurgitation (AR). Vesnarinone, a positively inotropic quinolone derivative, suppresses survival of fibroblasts (CF) from hearts with chronic experimental AR. To explore further the potential effects of vesnarinone on cardiac fibrosis in AR, we tested the hypothesis that vesnarinone suppresses gene expression induced by AR in CF. Differentially expressed genes were isolated by suppression subtractive hybridization (SSH) in CF from hearts of 2 New Zealand White rabbits with surgically induced AR compared with 2 normal rabbits. In cultured AR-CF treated with and without vesnarinone (4 doses, including the dose that had caused maximal survival suppression in cultured AR-CF), drug effect was assessed on expression of genes found to be up-regulated by AR. SSH, reverse Northern analysis, and Northern analysis indicated that at doses several orders of magnitude lower than those used for treatment in CHF vesnarinone significantly down-regulated 2 genes (thrombospondin 1, annexin II) up-regulated by AR. The study confirmed earlier findings of AR-mediated alteration in expression of genes that code for noncollagen extracellular matrix (ECM) proteins. Thus,...Continue Reading

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