氯贝丁酯对脑血管内皮细胞过氧化物酶体增殖物激活受体α表达及一氧化氮生成的调节作用

Regulation of cerebrovascular endothelial peroxisome proliferator activator receptor alpha expression and nitric oxide production by clofibrate.

作者信息

Yakubu Momoh A, Nsaif Rami H, Oyekan Adebayo O

机构信息

Vascular Biology Unit, Center for Cardiovascular Diseases, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 77004, USA.

出版信息

Bratisl Lek Listy. 2010;111(5):258-64.

PMID:20568414

Abstract

BACKGROUND

Peroxisome proliferator activator receptor alpha (PPAR alpha), a member of the nuclear receptor superfamily, is known to increase nitric oxide (NO) production and the mechanisms by which PPAR alpha activation alleviates vascular dysfunction may predicate its activation and possible expression.

OBJECTIVES

We have evaluated the effects of acute clofibrate, a PPAR alpha ligand and the role of PKC on PPAR alpha expression and NO production in cultured cerebral microvascular endothelial cell (CMVEC).

METHODS

Confluent CMVEC derived from pig brain were cultured and the role of PKC in acute clofibrate-induced PPAR alpha expression and NO production was determined in the presence or absence of PKC activator phorbol myristate acetate (PMA) or inhibitor (calphostin C).

RESULTS

Incubation of CMVEC with clofibrate or PMA increased NO production by 40% or 27%, respectively, whereas co-incubation of cells with PMA and clofibrate had no effect on NO production. Incubation of cells with Calphostin C blunted PMA but not clofibrate-induced increase in NO production. L-NAME (0.1 mM), an inhibitor of NO synthase, reduced basal (47%; p<0.01) and abolished clofibrate-induced increase in NO production. Clofibrate increased PPAR alpha expression (26%; p<0.05) while PMA with or without clofibrate reduced PPAR alpha expression (p<0.01). On the other hand, calphostin C reduced basal (69%, ap<0.01) as well as clofibrate-induced increase (59%, p<0.01) in PPAR expression, and further reduced PMA-induced down regulation of PPAR expression. eNOS expression was not significantly affected by either clofibrate or PMA, alone or in combination.

CONCLUSION

These results show that in the brain microvascular endothelial cell, PPAR alpha activation increases NO production-independent of eNOS and PKC signaling pathways, a regulates PPAR alpha expression through a complex PKC signaling mechanism(s) as both PKC activation and inhibition reduced clofibrate-induced activation of PPAR expression (Fig. 4, Ref. 32). Full Text (Free, PDF) www.bmj.sk.

摘要

背景

过氧化物酶体增殖物激活受体α（PPARα）是核受体超家族的成员之一，已知其可增加一氧化氮（NO）的生成，PPARα激活减轻血管功能障碍的机制可能决定其激活及可能的表达。

目的

我们评估了PPARα配体氯贝丁酯急性作用的效果以及蛋白激酶C（PKC）在培养的脑微血管内皮细胞（CMVEC）中对PPARα表达和NO生成的作用。

方法

培养源自猪脑的融合CMVEC，在存在或不存在PKC激活剂佛波酯（PMA）或抑制剂（钙泊三醇C）的情况下，确定PKC在氯贝丁酯急性诱导的PPARα表达和NO生成中的作用。

结果

氯贝丁酯或PMA孵育CMVEC分别使NO生成增加40%或27%，而细胞用PMA和氯贝丁酯共同孵育对NO生成无影响。用钙泊三醇C孵育细胞可减弱PMA诱导但不能减弱氯贝丁酯诱导的NO生成增加。NO合酶抑制剂L - NAME（0.1 mM）降低基础NO生成（47%；p<0.01）并消除氯贝丁酯诱导的NO生成增加。氯贝丁酯增加PPARα表达（26%；p<0.05），而无论有无氯贝丁酯的PMA均降低PPARα表达（p<0.01）。另一方面，钙泊三醇C降低基础PPAR表达（69%，p<0.01）以及氯贝丁酯诱导的增加（59%，p<0.01），并进一步降低PMA诱导的PPAR表达下调。单独或联合使用氯贝丁酯或PMA对内皮型一氧化氮合酶（eNOS）表达均无显著影响。