Renin-angiotensin system inhibitors suppress azoxymethane-induced colonic preneoplastic lesions in C57BL/KsJ-db/db obese mice
Renin-angiotensin system inhibitors suppress azoxymethane-induced colonic preneoplastic lesions in C57BL/KsJ-db/db obese mice
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DOI：
10.1016/j.bbrc.2011.05.115
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发表时间：
2011-06-24
影响因子：
3.1
通讯作者：
Moriwaki, Hisataka
中科院分区：
文献类型：
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作者：
Kubota, Masaya;Shimizu, Masahito;Moriwaki, Hisataka
与肥胖相关的代谢异常，包括慢性炎症和氧化应激，会增加结直肠癌的风险。肾素-血管紧张素系统 (RAS) 的失调在肥胖相关代谢紊乱和多种癌症发生中也发挥着关键作用。在本研究中，我们研究了血管紧张素转换酶 (ACE) 抑制剂和血管紧张素 II 1 型受体阻滞剂 (ARB)（两者均抑制 RAS）对 C57BL/KsJ-db/db (db/db) 肥胖小鼠中氧化偶氮甲烷 (AOM) 引发的结肠癌前病变发展的影响。雄性 db/db 小鼠每周皮下注射 AOM（15 mg/kg 体重）4 次，然后饮用含有卡托普利（ACE 抑制剂，5 mg/kg/天）或替米沙坦（ARB，5 mg/kg/天）的饮用水，持续 7 周。处死时，与对照组观察到的结果相比，给予卡托普利或替米沙坦显着减少了结肠癌前病变的总数，即异常隐窝病灶和β-连环蛋白积累的隐窝。卡托普利和替米沙坦降低了 AOM 处理的 db/db 小鼠结肠粘膜中 TNF-α mRNA 的表达水平。卡托普利降低了这些小鼠白色脂肪组织中 TNF-α、IL-1β、IL-6 和 PAI-1 mRNA 的表达水平，而替米沙坦降低了这些小鼠白色脂肪组织中 COX-2、IL-1β、IL-6 和 PAI-1 mRNA 的表达水平。此外，这些药物显着降低了实验小鼠尿液中 8-OHdG 的水平，8-OHdG 是 DNA 氧化损伤的替代标志物。这些发现表明，ACE 抑制剂和 ARB 均通过减轻肥胖小鼠的慢性炎症和氧化应激来抑制化学诱导的结肠癌发生。因此，针对 RAS 失调可能是肥胖个体结直肠癌化学预防的有效策略。 (C) 2011 Elsevier Inc. 保留所有权利。
Obesity-related metabolic abnormalities, including chronic inflammation and oxidative stress, increase the risk of colorectal cancer. Dysregulation of the renin-angiotensin system (RAS) also plays a critical role in obesity-related metabolic disorders and in several types of carcinogenesis. In the present study, we examined the effects of an angiotensin-converting enzyme (ACE) inhibitor and angiotensin-II type 1 receptor blocker (ARB), both of which inhibit the RAS, on the development of azoxymethane (AOM)-initiated colonic premalignant lesions in C57BL/KsJ-db/db (db/db) obese mice. Male db/db mice were given 4 weekly subcutaneous injections of AOM (15 mg/kg body weight), and then, they received drinking water containing captopril (ACE inhibitor, 5 mg/kg/day) or telmisartan (ARB, 5 mg/kg/day) for 7 weeks. At sacrifice, administration of either captopril or telmisartan significantly reduced the total number of colonic premalignant lesions, i.e., aberrant crypt foci and beta-catenin accumulated crypts, compared to that observed in the control group. The expression levels of TNF-alpha mRNA in the colonic mucosa of AOM-treated db/db mice were decreased by captopril and telmisartan. Captopril lowered the expression levels of TNF-alpha, IL-1 beta, IL-6, and PAI-1 mRNAs, while telmisartan lowered the expression levels of COX-2, IL-1 beta, IL-6, and PAI-1 mRNAs in the white adipose tissues of these mice. In addition, these agents significantly reduced the levels of urinary 8-OHdG, a surrogate marker of oxidative damage to DNA, in the experimental mice. These findings suggested that both ACE inhibitor and ARB suppress chemically-induced colon carcinogenesis by attenuating chronic inflammation and reducing oxidative stress in obese mice. Therefore, targeting dysregulation of the RAS might be an effective strategy for chemoprevention of colorectal carcinogenesis in obese individuals. (C) 2011 Elsevier Inc. All rights reserved.