05 vs. baseline). Losartan also reduced Volasertib cancer the expression of two important mediators of liver fibrogenesis such as ut-PA (?40%, P < 0.05 vs. baseline) and MMP-2 (?27%, P < 0.05 vs. baseline). Table 5. Hepatic expression of genes involved in liver fibrogenesis in normal livers compared with patients with CHC before and after treatment with losartan Changes in hepatic gene expression nonphagocytic NOX components after treatment with oral losartan. We previously demonstrated that nonphagocytic NOX plays a key role in liver fibrosis and is stimulated by angiotensin II (6, 12). Therefore, we examined whether AT1 receptor blockade downregulates the expression of key components of this system in patients with CHC.
As shown in Table 5, losartan treatment was associated with a significant decrease in the expression of key components of nonphagocytic NOX complex such as NOXO-1 (?29%), NOXA-1 (?26%), and Rac-1 (?19%). NOXO-1, the homologue of p47phox, and Rac-1 are crucial components of the NOX complex in HSC (15). Interestingly, the decrease of Rac-1 strongly correlated with the decrease of procollagen ��1(I) (r = 0.684, P = 0.001), procollagen ��1(IV) (r = 0.797, P = 0.001), and ut-PA (r = 0.689, P = 0.009). Since NOX mediates angiotensin II fibrogenic activity in the liver, the decrease in expression of key components of NOX and procollagen supports an antifibrogenic effect of losartan. The expression of CYP2E1 (?22%) and catalase (?18%) decreased after treatment with losartan while expression of SOD-2 and HO-1 remained unchanged. We did not detect expression of NOX-1, NOX-3, and NOX-5 in the liver before or after losartan.
Changes in hepatic gene expression in patients with decreased liver fibrosis. We observed that patients with improvement in liver fibrosis had higher expression of AT1 receptor at baseline compared with patients without improvement in liver fibrosis (mean 2?����Ct AT1 receptor expression 2.39 �� 0.69 vs. 1.38 �� 0.44 in responders vs. nonresponders, respectively; P = 0.004). We next analyzed changes in gene expression vs. baseline in patients with improved liver fibrosis after treatment compared with patients without improvement in liver fibrosis. As shown in Table 6, patients with improvement in liver fibrosis showed a pronounced downregulation of genes encoding extracellular matrix proteins, profibrogenic genes, and NOX genes. In contrast, no changes in hepatic gene expression were Cilengitide found in those patients without fibrosis improvement. These results suggest that changes in hepatic gene expression could decrease collagen accumulation in patients with CHC. Table 6. Changes in hepatic expression of fibrogenic genes vs.
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