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 Western world, especially in the elderly. Myocardial fibrosis induced by activated cardiac fibroblasts is thought to play a key role in the pathogenesis 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 was shown by Western blotting. In addition, the expression of genes of the extracellular matrix proteins, metalloproteases (MMPs), their inhibitors, and TGF-beta were analyzed by semiquantitative PCR. Activation of MMPs were controlled 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-kinase, the extracellular regulated kinases (ERKs), the jun kinase (JNK), as well as transcription factors like ATF-2 and NF-kappaB. In addition, the expression and activation of MMP-2, MMP-9, and MMP-13 were induced, which may be responsible for tissue remodeling followed by fibrosis. Conclusion: Due to their effects on the expression and activation of metalloproteases, AGES should be regarded as a potential therapeutic target for the prevention of pathologic remodeling.