Abstract
Background and AimsHepatitis C virus (HCV) infection is associated with systemic oxidative stress. Since the heme catabolic pathway plays an important role in antioxidant protection, we attempted to assess the gene expression of key enzymes of heme catabolism, heme oxygenase 1 (HMOX1), heme oxygenase 2 (HMOX2), and biliverdin reductase A (BLVRA) in the liver and peripheral blood leukocytes (PBL) of patients chronically infected with HCV.MethodsGene expressions (HMOX1, HMOX2, BLVRA) and HCV RNA were analyzed in PBL of HCV treatment naïve patients (n = 58) and controls (n = 55), with a subset of HCV patients having data on hepatic gene expression (n = 35). Based upon the therapeutic outcome, HCV patients were classified as either responders (n = 38) or treatment-failure patients (n = 20). Blood samples in HCV patients were collected at day 0, and week 12, 24, 36, and 48 after the initiation of standard antiviral therapy.ResultsCompared to the controls, substantially increased BLVRA expression was detected in PBL (p<0.001) of therapeutically naïve HCV patients. mRNA levels of BLVRA in PBL closely correlated with those in liver tissue (r2 = 0.347,p = 0.03). A marked difference in BLVRA expression in PBL between the sustained responders and patients with treatment failure was detected at week 0 and during the follow-up (p<0.001). Multivariate analysis revealed that BLVRA basal expression in PBL was an independent predictor for sustained virological response (OR 15; 95% CI 1.05–214.2; P = 0.046). HMOX1/2 expression did not have any effect on the treatment outcome.ConclusionOur results suggest that patients with chronic HCV infection significantly upregulate BLVRA expression in PBL. The lack of BLVRA overexpression is associated with non-responsiveness to standard antiviral therapy; whereas, HMOX1/2 does not seem to have any predictive potential.
Highlights
Hepatitis C virus (HCV) infection represents one of the leading causes of chronic hepatitis worldwide, resulting in progression into fibrosis, cirrhosis and hepatocellular carcinoma in a significant number of HCV-infected patients [1]
HCV is mainly hepatotropic, there is evidence that it can replicate in the peripheral blood mononuclear cells (PBMC) of patients with chronic HCV infection [5]
An accumulating body of evidence suggests that heme oxygenase 1 (HMOX1) overexpression contributes to cellular response against oxidative stress [13], and might have strong anti-fibrotic, as well as an antiapoptotic potential within the liver tissue [14,15]
Summary
Hepatitis C virus (HCV) infection represents one of the leading causes of chronic hepatitis worldwide, resulting in progression into fibrosis, cirrhosis and hepatocellular carcinoma in a significant number of HCV-infected patients [1]. Two HMOX isoforms have evolved, which include HMOX1 (OMIM*141250), an inducible isoenzyme, and HMOX2 (OMIM*141251), a constitutive isoform Both catalyze the same reaction, but are differentially regulated, and play different roles in protecting tissues against oxidative injuries [12]. On the other hand, reduced HMOX1 expression has been reported in the liver tissue of patients with chronic hepatitis C [8]; under in vitro conditions hepatic HMOX1 overexpression in the presence of HCV proteins has been reported by other authors [17]. Since the heme catabolic pathway plays an important role in antioxidant protection, we attempted to assess the gene expression of key enzymes of heme catabolism, heme oxygenase 1 (HMOX1), heme oxygenase 2 (HMOX2), and biliverdin reductase A (BLVRA) in the liver and peripheral blood leukocytes (PBL) of patients chronically infected with HCV
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