Abstract
Background and aims: Decreased nitric oxide (NO) bioavailability in a cirrhotic liver contributes to high intrahepatic vascular resistance (IHVR) and portal hypertension (PHT). Nostrin is an inhibitory protein of NO synthesising enzyme endothelial NO synthase (eNOS), shown to increase in cirrhosis with PHT, however, the precise molecular mechanism is poorly documented. This study aimed to elucidate the role of Nostrin and associated derangement in hepatic NO generation in cirrhotic liver. Further, we investigate whether Nostrin could be a biomarker in the progression of cirrhosis. Methods: The study was conducted in sixty healthy subjects and 120 cirrhotic patients (both compensated and decompensated) to analyze the blood Nostrin, cGMP and cytokine levels. In addition, liver tissue samples collected from cirrhotic patients were used for the analysis of gene and protein expression of Nostrin, eNOS and inflammatory markers.
Results:When compared to healthy controls, systemic levels of Nostrin and cGMP were elevated in compensated cirrhosis. In decompensated cirrhosis, further robust increases in Nostrin and cGMP were noted. Furthermore, hepatic Nostrin expression was considerably higher whilst reduced eNOS activity and hepatic cGMP levels in cirrhotic liver compared to control liver. Hepatic iNOS and NF kB protein expression were significantly increased in cirrhotic liver compared to control liver.
Conclusions: In decompensated cirrhotic patients, a robust increase in hepatic Nostrin expression was associated with inflammation and thus, reduced eNOS activity with concomitant local NO generation. Furthermore, Blood Nostrin concentration was higher and parallel to disease severity and could be a key diagnostic and prognostic biomarker in cirrhotic patients with exacerbated PHT.