Lee Kuy-Sook, Park Jin-Hee, Lee Seahyoung, Lim Hyun-Joung, Park Hyun-Young
Division of Cardiovascular and Rare Diseases, Center for Biomedical Sciences, National Institute of Health, Seoul, Korea.
J Cell Biochem. 2009 Apr 1;106(5):823-34. doi: 10.1002/jcb.22038.
Peroxisome proliferator-activated receptors delta (PPARdelta) is known to be expressed ubiquitously, and the predominant PPAR subtype of cardiac cells. However, relatively less is known regarding the role of PPARdelta in cardiac cells except that PPARdelta ligand treatment protects cardiac hypertrophy by inhibiting NF-kappaB activation. Thus, in the present study, we examined the effect of selective PPARdelta ligand L-165041 on angiotensin II (AngII) induced cardiac hypertrophy and its underlying mechanism using cardiomyocyte. According to our data, L-165041 (10 microM) inhibited AngII-induced [(3)H] leucine incorporation, induction of the fetal gene atrial natriuretic factor (ANF) and increase of cardiomyocyte size. Previous studies have implicated the activation of focal adhesion kinase (FAK) in the progress of cardiomyocyte hypertrophy. L-165041 pretreatment significantly inhibited AngII-induced intracellular Ca(2+) increase and subsequent phosphorylation of FAK. Further experiment using Ca(2+) ionophore A23187 confirmed that Ca(2+) induced FAK phosphorylation, and this was also blocked by L-165041 pretreatment. In addition, overexpression of PPARdelta using adenovirus significantly inhibited AngII-induced intracellular Ca(2+) increase and FAK expression, while PPARdelta siRNA treatment abolished the effect of L-165041. These data indicate that PPARdelta ligand L-165041 inhibits AngII induced cardiac hypertrophy by suppressing intracellular Ca(2+)/FAK/ERK signaling pathway in a PPARdelta dependent mechanism.
已知过氧化物酶体增殖物激活受体δ（PPARδ）在全身广泛表达，是心脏细胞中主要的PPAR亚型。然而，除了PPARδ配体治疗通过抑制核因子κB（NF-κB）激活来保护心脏肥大外，关于PPARδ在心脏细胞中的作用相对了解较少。因此，在本研究中，我们使用心肌细胞研究了选择性PPARδ配体L-165041对血管紧张素II（AngII）诱导的心脏肥大及其潜在机制的影响。根据我们的数据，L-165041（10微摩尔）抑制了AngII诱导的[³H]亮氨酸掺入、胎儿基因心房钠尿肽（ANF）的诱导以及心肌细胞大小的增加。先前的研究表明，粘着斑激酶（FAK）的激活与心肌细胞肥大的进展有关。L-165041预处理显著抑制了AngII诱导的细胞内Ca²⁺增加以及随后的FAK磷酸化。使用Ca²⁺离子载体A23187的进一步实验证实，Ca²⁺诱导了FAK磷酸化，而L-165041预处理也能阻断这一过程。此外，使用腺病毒过表达PPARδ显著抑制了AngII诱导的细胞内Ca²⁺增加和FAK表达，而PPARδ小干扰RNA（siRNA）处理则消除了L-165041的作用。这些数据表明，PPARδ配体L-165041通过PPARδ依赖的机制抑制细胞内Ca²⁺/FAK/细胞外信号调节激酶（ERK）信号通路，从而抑制AngII诱导的心脏肥大。
