Effects of Different Doses of Statins on Liver Regeneration Through Angiogenesis and Possible Relation Between These Effects and Acute Phase Responses

Abstract

Background We examined the effects of two doses of statins on liver regeneration through angiogenesis and its possible relation to acute phase responses. Materials and Methods Seventy-two rats were randomly divided into three groups: controls; low-dose atorvastatin (0.5 mg/kg/d); high-dose atorvastatin (2.5 mg/kg/d). Statin was administered daily by oral gavage for 7 days. After atorvastatin treatment, all animals in the three groups underwent 70% hepatectomy. Thereafter animals were subdivided into three subgroups, to evaluate the characteristics of liver regeneration proliferating cell nuclear antigen (PCNA), angiogenesis (KDR/Flk-1 [vascular endothelial growth factor-2]) and acute phase response (serum interleukin [IL]-6) at 12, 24, and 72 hours. Results At the 24 hours posthepatectomy, low-dose compared with high-dose atorvastatin increased liver regeneration ( P = .004) and angiogenic responses compared also to controls ( P = .026 and P = .059). However, there appeared no difference in IL-6 expression ( P = .159). At the 72 hours posthepatectomy, low-dose atorvastatin treatment increased liver regeneration compared with controls ( P = .047), but it showed no significant difference from the high-dose treatment ( P = .109). Low doses of statin increased angiogenic responses compared with both control and high-dose animals ( P = .016 and P = .002). Moreover, the high-dose group displayed decreased angiogenic responses compared with the control group ( P = .044). Serum IL-6 expression was significantly greater among both low- and high-dose groups compared with controls ( P = .005 and P = .003, respectively). Conclusions Low-dose statin treatment increased KDR/Flk-1-dependent angiogenesis, which resulted in an increased regeneration response. In contrast, high-dose statin therapy decreased angiogenesis without affecting long-term regeneration responses. Finally, statin therapy may contribute to liver regeneration due to prolonged IL-6 expression independent of statin doses.