H-00340-2004.r1 1 Profibrotic Influence of High Glucose on Cardiac Fibroblast Functions: Effects of Losartan and Vitamin E

Long-standing diabetes can result in the development of a cardiomyopathy, which can be accompanied by myocardial fibrosis. Whereas exposure of cultured kidney and skin fibroblasts to high glucose (HG) is known to increase collagen synthesis, little is known about cardiac fibroblasts (CF). Therefore, we determined the influence of HG on CF functions, and the effects of losartan and vitamin E in these responses. We cultured rat CF in either normal (NG, 5.5 mM) or HG media (25 mM) and assessed changes in protein and collagen synthesis, matrix metalloproteinase (MMP) activity, and levels of mRNA for the angiotensin II type 1 (AT1) receptor. Results indicate that HG CF synthesized more protein and collagen and that the effects were not due to changes in osmotic pressure. The addition of angiotensin II (Ang II) stimulated protein and collagen synthesis in NG but not HG CF. Interestingly, losartan pre-treatment blocked the HGor Ang II-induced increases in both protein and collagen synthesis. HG or Ang II decreased total MMP activity. Decreases in MMP activity were blocked by losartan. AT1 mRNA levels were upregulated with HG. Vitamin E pre-treatment blocked HG effects on total protein synthesis and stimulated MMP activity. Results suggest that HG may promote fibrosis by increasing CF protein and collagen synthesis and decreasing MMP activity. HG may cause these effects via the upregulation of AT1 receptors, which can be blocked by losartan. However, vitamin E can alter HG-induced changes in CF functions independently of AT1 mRNA levels.