Cardioprotective mechanism of telmisartan via PPAR-γ-eNOS pathway in Dahl salt-sensitive hypertensive rats
Cardioprotective mechanism of telmisartan via PPAR-γ-eNOS pathway in Dahl salt-sensitive hypertensive rats
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DOI：
10.1038/ajh.2008.27
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发表时间：
2008-05-01
影响因子：
3.2
通讯作者：
Matsuoka, Hiroaki
中科院分区：
文献类型：
--
作者：
Kobayashi, Naohiko;Ohno, Tomoyuki;Matsuoka, Hiroaki
最近，一些研究人员发现替米沙坦是一种血管紧张素II （Ang II）受体阻滞剂（ARB），是过氧化物酶体增殖激活受体γ (PPAR-y)的部分激动剂。我们研究替米沙坦是否通过ppar - γ改善与内皮型一氧化氮合酶（eNCS）产生相关的心血管重塑，抑制rho激酶途径，并抑制达尔盐敏感（DS）高血压大鼠的氧化应激。方法从6-11周龄开始给药替米沙坦（1mg /kg /天）或替米沙坦加ppar - γ抑制剂GW9662（1mg /kg /天）。以同龄雄性达尔耐盐（DR）大鼠为对照组。结果DS大鼠ens、ppar - γ表达水平及eNOS磷酸化水平明显低于DR大鼠。慢性替米沙坦治疗对DS大鼠的这些指标均有显著性提高，但替米沙坦加GW9662组无显著性提高。替米沙坦能有效抑制血管病变形成，如内侧增厚和血管周围纤维化，而替米沙坦加GW9662不能有效抑制血管病变形成。此外，替米沙坦降低了DS大鼠RhoA蛋白、rhok mRNA和肌球蛋白轻链磷酸化的上调，其程度与选择性rhok激酶抑制剂Y-27632治疗后相似。此外，替米沙坦还能抑制DS大鼠NAD(P)H氧化酶p22phox、p47phox、gp91 phox的表达以及丝裂原活化蛋白激酶及其下游效应物p70 S6激酶的磷酸化。结论替米沙坦的心脏保护机制可能与ppar - γ - enos、氧化应激和rho激酶途径相关的内皮功能改善有关。
BACKGROUNDRecently, some investigators have shown that telmisartan, an angiotensin II (Ang II)-receptor blocker (ARB), is a partial agonist of the peroxisome proliferator-activated receptor-gamma (PPAR-y). We investigate whether telmisartan improves cardiovascular remodeling associated with the production of endothelial nitric oxide synthase (eNCS) through PPAR-gamma, inhibits the Rho-kinase pathway, and suppresses oxidative stress in Dahl salt-sensitive (DS) hypertensive rats.METHODSTelmisartan (1 mg/kg per day) or telmisartan plus PPAR-gamma inhibitor, GW9662(1 mg/kg per day) was administered from the age of 6-11 weeks. Age-matched male Dahl salt-resistant (DR) rats served as a control group.RESULTSThe levels of eNCS and PPAR-gamma expression, and eNOS phosphorylation were significantly lower in DS rats than in DR rats. the Chronic telmisartan treatment in DS rats significantly increased these parameters, but not telmisartan plus GW9662. Telmisartan effectively inhibited the vascular lesion formation such as medial thickness and perivascular fibrosis, but not telmisartan plus GW9662. Moreover, upregulated RhoA protein, Rho-kinase mRNA, and myosin light-chain phosphorylation in DS rats was decreased by telmisartan to a similar degree as observed after treatment with Y-27632, a selective Rho-kinase inhibitor. In addition, NAD(P)H oxidase p22phox, p47phox, gp91 phox expression, and mitogen-activated protein kinase and its downstream effector p70 S6 kinase phosphorylation in DS rats was also inhibited by telmisartan.CONCLUSIONSThese results suggest that the cardioprotective mechanism of telmisartan may be partly due to improvement of endothelial function associated with PPAR-gamma-eNOS, oxidative stress, and Rho-kinase pathway.