Statins and Portal Hypertension: Mechanisms of Statin-mediated Reduction in Portal Hypertension
Clinical and experimental preclinical studies have demonstrated that statins decrease portal hypertension through reducing intrahepatic vascular resistance. Increased intrahepatic vascular resistance is partly mediated by sinusoidal endothelial dysfunction driven by impaired endothelial nitric oxide synthase (eNOS) activity and increased sensitivity to endogenous vasoconstrictors. Upregulated rho-kinase activity has been demonstrated in animal models of cirrhosis and in human liver tissue and may be responsible for this phenomenon. Activation of this pathway inhibits myosin light chain phosphatase leading to a relative increase in phosphorylation of myosin light chains and increased vascular smooth muscle activity. Rho-kinase activation also suppresses eNOS expression and activity, further increasing vascular smooth muscle activity.
Statins directly interfere with the formation of isoprenoid intermediates such as geranylgeranylpyrophosphate, which are required for membrane translocation of rhoA, a critical step in the rho-kinase pathway. Trebicka et al used a bile duct ligation model of cirrhosis in rats to characterise the action of atorvastatin on hepatic vascular resistance. Molecular analysis revealed increased intrahepatic rho-kinase total protein levels in cirrhotic animals, but markedly decreased rho-kinase activity among animals treated with atorvastatin. Animals treated with atorvastatin also had increased eNOS expression compared with controls. Portal pressures were significantly decreased (>20% reduction, p<0.05) among animals treated with atorvastatin compared with controls with no difference in splanchnic or systemic vascular resistance. A study using a CCL4 model of cirrhosis in mice demonstrated reduced volume expansion-induced increases in portal pressure in animals treated with simvastatin compared with placebo. Collectively, these results suggest that statins induce selective vasodilatation of the microvasculature in the cirrhotic liver. The ability of statins to selectively target hepatic microvasculature may offer a clinical advantage over other pharmacological therapies used to reduce portal hypertension (β-blockers, nitrates) that can worsen systemic haemodynamics.