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Effects of PPAR-α silence on ET-1 induced myocardial hypertrophy and PI3K/Akt/GSK3β-NFATc4 signal pathway / 中国病理生理杂志
Chinese Journal of Pathophysiology ; (12): 2289-2294, 2009.
Article Dans Chinois | WPRIM | ID: wpr-404998
ABSTRACT

AIM:

To investigate the role and signal mechanism of PPAR-α in the pathogenesis of cardiac hypertrophy.

METHODS:

Small interfering RNA (siRNA) was applied to efficiently silence the gene expression of PPAR-α in cardiac myocytes. [~3H] leucine incorporation assay was performed to measure protein synthesis. Reverse transcription-polymerase chain reaction (RT-PCR) was used to analyze the mRNA level of atrial natriuretic factor (ANF) and PPAR-α. Western blotting analysis was performed to investigate the levels of phosphorylation of protein kinase B (PKB/Akt) and glycogen synthase kinase 3β (GSK3β). Immunofluorescence analysis was used to examine the cellular localization of NFATc4.

RESULTS:

(1)RSS304168 was the most efficient stealth RNAi duplex to specifically inhibit PPAR-α expression. (2)RSS304168 significantly potentiated the ET-1-induced cardiomyocyte hypertrophy and enhanced ET-1-induced protein synthesis and ANF mRNA expression in cardiomyocytes. Moreover, RSS304168 completely reversed the inhibitory effects of fenofibrate on ET-1-induced protein synthesis and ANF mRNA expression. (3)RSS304168 enhanced ET-1-induced phosphorylation of Akt at Ser473 and GSK3β at Ser9. The effects of ET-1 or ET-1 combined with RSS304168 on phosphorylation of Akt/GSK3β were completely blocked by LY294002, a PI3K specific inhibitor. Fenofibrate markedly inhibited ET-1-induced phosphorylation of Akt/GSK3β while RSS304168 abolished these effects of fenofibrate. (4)Fenofibrate prevented the nuclear translocation of NFATc4 induced by ET-1 while RSS304168 abolished this effect of fenofibrate.

CONCLUSION:

Activation of PPAR-α inhibits ET-1-induced cardiomyocyte hypertrophy through blocking Akt/GSK3β-NFATc4 signaling pathways.

Texte intégral: Disponible Indice: WPRIM (Pacifique occidental) langue: Chinois Texte intégral: Chinese Journal of Pathophysiology Année: 2009 Type: Article

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Texte intégral: Disponible Indice: WPRIM (Pacifique occidental) langue: Chinois Texte intégral: Chinese Journal of Pathophysiology Année: 2009 Type: Article