Advanced glycation endproducts: Activators of cardiac remodeling in primary fibroblasts from adult rat hearts

Background: Cardiovascular diseases are the leading cause of death in the W estern world, especially in the elderly. Myocardial fibrosis induced by act ivated cardiac fibroblasts is thought to play a key role in the pathogenesi s of cardiovascular disease. Accumulation of advanced glycation endproducts (AGES), products of nonenzymatic glycation of proteins, correlate with the stiffness of the heart and large vessels. To elucidate a potential role of AGES as a trigger of fibrosis, the effects of AGES on primary fibroblasts from hearts of adult rats were investigated. Material and Methods: The activation of intracellular signaling pathways wa s shown by Western blotting. In addition, the expression of genes of the ex tracellular matrix proteins, metalloproteases (MMPs), their inhibitors, and TGF-beta were analyzed by semiquantitative PCR. Activation of MMPs were co ntrolled by Zymography. Results: It was shown that treatment of cardiac fibroblasts with AGES leads to an activation of different signaling molecules, such as the p38MAP-kina se, the extracellular regulated kinases (ERKs), the jun kinase (JNK), as we ll as transcription factors like ATF-2 and NF-kappaB. In addition, the expr ession and activation of MMP-2, MMP-9, and MMP-13 were induced, which may b e responsible for tissue remodeling followed by fibrosis. Conclusion: Due to their effects on the expression and activation of metall oproteases, AGES should be regarded as a potential therapeutic target for t he prevention of pathologic remodeling.