Li Ruifang, Zheng Wenhua, Pi Rongbiao, Gao Jie, Zhang Huijie, Wang Ping, Le Kang, Liu Peiqing
Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, PR China.
FEBS Lett. 2007 Jul 10;581(17):3311-6. doi: 10.1016/j.febslet.2007.06.017. Epub 2007 Jun 19.
Activation of peroxisome proliferator-activated receptor-alpha (PPAR-alpha) has been recently reported to inhibit vascular inflammatory response and prevent cardiac hypertrophy. However, it is unclear how the activation of PPAR-alpha regulates hypertrophic response. In the present study, we found that application of fenofibrate and overexpression of PPAR-alpha inhibited endothelin-1 (ET-1)-induced phosphorylation of protein kinase B (Akt) at Ser473 and glycogen synthase kinase3beta (GSK3beta) at Ser9, and prevented ET-1-induced nuclear translocation of NFATc4 in cardiomyocytes. Moreover, co-immunoprecipitation studies showed that fenofibrate strongly induced the association of nuclear factor of activated T cells (NFATc4) with PPAR-alpha. These results suggest that activation of PPAR-alpha inhibits ET-1-induced cardiac hypertrophy through regulating PI3K/Akt/GSK3beta and NFAT signaling pathways.
最近有报道称，过氧化物酶体增殖物激活受体α（PPAR-α）的激活可抑制血管炎症反应并预防心脏肥大。然而，尚不清楚PPAR-α的激活如何调节肥大反应。在本研究中，我们发现应用非诺贝特和过表达PPAR-α可抑制内皮素-1（ET-1）诱导的蛋白激酶B（Akt）在Ser473位点的磷酸化以及糖原合酶激酶3β（GSK3β）在Ser9位点的磷酸化，并阻止ET-1诱导的心肌细胞中NFATc4的核转位。此外，免疫共沉淀研究表明，非诺贝特强烈诱导活化T细胞核因子（NFATc4）与PPAR-α的结合。这些结果表明，PPAR-α的激活通过调节PI3K/Akt/GSK3β和NFAT信号通路来抑制ET-1诱导的心脏肥大。
