Colakoglu T, Nursal T Z, Ezer A, Kayaselcuk F, Parlakgumus A, Belli S, Karakayali H, Haberal M
Department of General Surgery, Faculty of Medicine, Baskent University, Ankara, Turkey.
Transplant Proc. 2010 Nov;42(9):3823-7. doi: 10.1016/j.transproceed.2010.09.004.
We examined the effects of two doses of statins on liver regeneration through angiogenesis and its possible relation to acute phase responses.
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.
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).
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.
我们通过血管生成研究了两种剂量的他汀类药物对肝脏再生的影响及其与急性期反应的可能关系。
72只大鼠随机分为三组：对照组；低剂量阿托伐他汀（0.5毫克/千克/天）；高剂量阿托伐他汀（2.5毫克/千克/天）。他汀类药物每日经口灌胃给药7天。阿托伐他汀治疗后，三组所有动物均接受70%肝切除术。此后，将动物再分为三个亚组，以评估肝再生增殖细胞核抗原（PCNA）、血管生成（KDR/Flk-1[血管内皮生长因子-2]）和急性期反应（血清白细胞介素[IL]-6）在12、24和72小时的特征。
肝切除术后2小时，与高剂量阿托伐他汀相比，低剂量阿托伐他汀增加了肝脏再生（P = 0.004），与对照组相比，血管生成反应也增加（P = 0.026和P = 0.059）。然而，IL-6表达没有差异（P = 0.159）。肝切除术后72小时，与对照组相比，低剂量阿托伐他汀治疗增加了肝脏再生（P = 0.047），但与高剂量治疗相比无显著差异（P = 0.109）。与对照组和高剂量组动物相比，低剂量他汀类药物增加了血管生成反应（P = 0.016和P = 0.002）。此外，高剂量组与对照组相比，血管生成反应降低（P = 0.044）。与对照组相比，低剂量和高剂量组的血清IL-明显更高（分别为P = 0.005和P = 0.003）。
低剂量他汀类药物治疗增加了KDR/Flk-1依赖性血管生成，从而导致再生反应增加。相比之下，高剂量他汀类药物治疗减少了血管生成，而不影响长期再生反应。最后，他汀类药物治疗可能由于IL-6表达延长而促进肝脏再生，与他汀类药物剂量无关。
