Rho-kinase inhibition ameliorates metabolic disorders through activation of AMPK pathway in mice.
Rho-kinase inhibition ameliorates metabolic disorders through activation of AMPK pathway in mice.
复制标题
DOI：
10.1371/journal.pone.0110446
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Shimokawa H
中科院分区：
文献类型：
--
作者：
Noda K;Nakajima S;Godo S;Saito H;Ikeda S;Shimizu T;Enkhjargal B;Fukumoto Y;Tsukita S;Yamada T;Katagiri H;Shimokawa H
由热量摄入过多和体力活动不足引起的代谢紊乱是重要的心血管危险因素。rho激酶是小gtp结合蛋白RhoA的效应蛋白，是重要的心血管治疗靶点，其活性在代谢综合征患者中升高。我们的目的是研究rho激酶抑制是否会改善高脂肪饮食（HFD）诱导的代谢紊乱，如果是这样，则阐明amp活化激酶（AMPK）的参与，AMPK是代谢状况的关键分子。小鼠喂食高脂肪饮食，导致代谢表型，如肥胖、高胆固醇血症和葡萄糖耐受不良。这些表型被选择性rho激酶抑制剂抑制，与全身氧气消耗增加和骨骼肌和肝脏AMPK激活有关。此外，rho激酶抑制增加了脂肪酸氧化、线粒体能量产生和葡萄糖代谢相关分子的mRNA表达，这些分子都是AMPK在这些组织中的靶点。在rho激酶显性阴性小鼠的全身过表达中，体重、血脂水平和葡萄糖代谢均较同窝对照小鼠有所改善。此外，在AMPKα2缺陷小鼠中，rho激酶抑制剂法舒地尔对体重、高胆固醇血症、AMPK靶点mRNA表达和全身氧气消耗增加的有益作用不存在，而法舒地尔则使葡萄糖代谢恢复到野生型小鼠的水平。在培养的小鼠肌细胞中，rho激酶的药理和遗传抑制通过肝激酶b1 （LKB1）增加AMPK活性，上调其靶点，而AMPK抑制剂化合物c会消除这种作用。这些结果表明，rho激酶抑制通过激活LKB1/AMPK通路改善代谢紊乱，表明rho激酶也是代谢紊乱的新治疗靶点。
Metabolic disorders, caused by excessive calorie intake and low physical activity, are important cardiovascular risk factors. Rho-kinase, an effector protein of the small GTP-binding protein RhoA, is an important cardiovascular therapeutic target and its activity is increased in patients with metabolic syndrome. We aimed to examine whether Rho-kinase inhibition improves high-fat diet (HFD)-induced metabolic disorders, and if so, to elucidate the involvement of AMP-activated kinase (AMPK), a key molecule of metabolic conditions. Mice were fed a high-fat diet, which induced metabolic phenotypes, such as obesity, hypercholesterolemia and glucose intolerance. These phenotypes are suppressed by treatment with selective Rho-kinase inhibitor, associated with increased whole body O2 consumption and AMPK activation in the skeletal muscle and liver. Moreover, Rho-kinase inhibition increased mRNA expression of the molecules linked to fatty acid oxidation, mitochondrial energy production and glucose metabolism, all of which are known as targets of AMPK in those tissues. In systemic overexpression of dominant-negative Rho-kinase mice, body weight, serum lipid levels and glucose metabolism were improved compared with littermate control mice. Furthermore, in AMPKα2-deficient mice, the beneficial effects of fasudil, a Rho-kinase inhibitor, on body weight, hypercholesterolemia, mRNA expression of the AMPK targets and increase of whole body O2 consumption were absent, whereas glucose metabolism was restored by fasudil to the level in wild-type mice. In cultured mouse myocytes, pharmacological and genetic inhibition of Rho-kinase increased AMPK activity through liver kinase b1 (LKB1), with up-regulation of its targets, which effects were abolished by an AMPK inhibitor, compound C. These results indicate that Rho-kinase inhibition ameliorates metabolic disorders through activation of the LKB1/AMPK pathway, suggesting that Rho-kinase is also a novel therapeutic target of metabolic disorders.
登录
查看更多内容
Sirtuins是否可行的目标可以改善健康状态和寿命？
DOI：
10.1038/nrd3738
发表时间：
2012-06-01
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Baur JA;Ungvari Z;Minor RK;Le Couteur DG;de Cabo R
通讯作者：
de Cabo R
影响因子：
37.8
作者：
Hattori, T;Shimokawa, H;Takeshita, A
通讯作者：
Takeshita, A
影响因子：
24
作者：
Liu, Ping-Yen;Chen, Jyh-Hong;Liao, James K.
通讯作者：
Liao, James K.
DOI：
10.1073/pnas.0705070104
发表时间：
2007-07-17
影响因子：
11.1
作者：
Jaeger, Sibylle;Handschin, Christoph;Spiegelman, Bruce M.
通讯作者：
Spiegelman, Bruce M.
影响因子：
64.8
作者：
Minokoshi, Y;Kim, YB;Kahn, BB
通讯作者：
Kahn, BB