Asbun Juan, Manso Ana Maria, Villarreal Francisco J
Department of Medicine, University of California at San Diego, La Jolla, USA.
Am J Physiol Heart Circ Physiol. 2005 Jan;288(1):H227-34. doi: 10.1152/ajpheart.00340.2004. Epub 2004 Sep 2.
Long-standing diabetes can result in the development of cardiomyopathy, which can be accompanied by myocardial fibrosis. Although exposure of cultured kidney and skin fibroblasts to high glucose (HG) concentration is known to increase collagen synthesis, little is known about cardiac fibroblasts (CFs). Therefore, we determined the influence of HG conditions on CF functions and the effects of losartan and vitamin E in these responses. We cultured rat CFs in either normal glucose (NG; 5.5 mM) or HG (25 mM) media and assessed changes in protein and collagen synthesis, matrix metalloproteinase (MMP) activity, and levels of mRNA for ANG II type 1 (AT(1)) receptors. Results indicate that HG-level CFs synthesized more protein and collagen, and these effects were not due to changes in osmotic pressure. The addition of ANG II stimulated protein and collagen synthesis in NG-concentration but not HG-concentration CFs. Interestingly, losartan pretreatment blocked the HG- or 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. AT(1) mRNA levels were upregulated with HG concentration. Vitamin E pretreatment blocked the effects of HG on total protein synthesis and stimulated MMP activity. Results suggest that HG levels may promote fibrosis by increasing CF protein and collagen synthesis and decreasing MMP activity. HG levels may cause these effects via the upregulation of AT(1) receptors, which can be blocked by losartan. However, vitamin E can alter HG concentration-induced changes in CF functions independently of AT(1) mRNA levels.
长期糖尿病可导致心肌病的发生，其可能伴有心肌纤维化。虽然已知培养的肾和皮肤成纤维细胞暴露于高葡萄糖（HG）浓度会增加胶原蛋白合成，但关于心脏成纤维细胞（CFs）的情况却知之甚少。因此，我们确定了HG条件对CF功能的影响以及氯沙坦和维生素E在这些反应中的作用。我们将大鼠CFs培养在正常葡萄糖（NG；5.5 mM）或HG（25 mM）培养基中，并评估蛋白质和胶原蛋白合成、基质金属蛋白酶（MMP）活性以及血管紧张素II 1型（AT(1)）受体的mRNA水平的变化。结果表明，HG水平的CFs合成了更多的蛋白质和胶原蛋白，且这些作用并非由渗透压变化引起。添加血管紧张素II刺激了NG浓度而非HG浓度CFs中的蛋白质和胶原蛋白合成。有趣的是，氯沙坦预处理可阻断HG或血管紧张素II诱导的蛋白质和胶原蛋白合成增加。HG或血管紧张素II降低了总MMP活性。MMP活性的降低被氯沙坦阻断。AT(1) mRNA水平随HG浓度上调。维生素E预处理可阻断HG对总蛋白质合成的影响并刺激MMP活性。结果表明，HG水平可能通过增加CF蛋白质和胶原蛋白合成以及降低MMP活性来促进纤维化。HG水平可能通过上调AT(1)受体导致这些作用，而氯沙坦可阻断该受体。然而，维生素E可独立于AT(1) mRNA水平改变HG浓度诱导的CF功能变化。
