Simvastatin ameliorates sinusoidal microcirculatory phenotype, fibrosis and portal hypertension in aged cirrhotic rats

Introduction: We have recently demonstrated that, due to an aggravation in the phenotype of sinusoidal cells, aged cirrhotic rats exhibit global exacerbation of cirrhosis compared to young animals. Although the mean age of... [ view full abstract ]

Introduction: We have recently demonstrated that, due to an aggravation in the phenotype of sinusoidal cells, aged cirrhotic rats exhibit global exacerbation of cirrhosis compared to young animals. Although the mean age of cirrhotic patients has increased, the beneficial effects of statins have only been studied in young cirrhotic animals. The present study evaluated the effects of simvastatin in aged cirrhotic rats, pre-clinical model closer to the real clinical practice.

Methods: 20 month-old cirrhotic rats received simvastatin (5mg/kd/day) or vehicle for 15 days. Liver microcirculatory phenotype was assessed by: hemodynamic studies, fibrosis, and sinusoidal phenotype markers in liver tissue and in primary LSEC and HSC. Moreover, bacterial translocation was evaluated.

Results: In comparison to vehicle-treated, aged cirrhotic rats receiving simvastatin showed a significant amelioration in liver microcirculation: -25% in portal pressure, -25% in hepatic vascular resistance, +130% vasodilatory capacity. Mechanisms underlying such improvements included significant reduction in fibrosis (-33%), LSEC improvement (-36% vWF, +55% Porosity, +83% KLF2), HSC de-activation (-35% α-SMA, -75% p-moesin, -35% contraction)  

and oxidative stress depletion (-71% O₂^-). Furthermore, improvement in hepatocytes phenotype was observed (+79% bile flow, bilirubin -56%, +42% cytochrome activity P4503A4, +49% HNF4α). Simvastatin did not alter bacterial translocation, nor caused toxic effects.

Conclusions: Simvastatin improves the hepatic sinusoidal microcirculation in aged cirrhotic rats, reinforcing the potential therapeutic effect of this vasoprotective drug in this sub-population of patients.