Pellieux Corinne, Montessuit Christophe, Papageorgiou Irène, Lerch René
Department of Internal Medicine, Cardiology Center, University Hospitals of Geneva, Geneva, Switzerland.
Pflugers Arch. 2007 Dec;455(3):443-54. doi: 10.1007/s00424-007-0297-0. Epub 2007 Jul 21.
Inactivation of peroxisome proliferator-activated receptor (PPARs) isoforms alpha, beta/delta, and gamma mediate distinct facets of hypertrophic transformation of adult cardiac myocytes. PPARs are ligand-activated transcription factors that modulate the transcriptional regulation of fatty acid metabolism and the hypertrophic response in neonatal cardiac myocytes. The purpose of this study was to determine the role of PPAR isoforms in the morphologic and metabolic phenotype transformation of adult cardiac myocytes in culture, which, in medium containing 20% fetal calf serum, undergo hypertrophy-like cell growth associated with downregulation of regulatory proteins of fatty acid metabolism. Expression and DNA-binding activity of PPARalpha, PPARbeta/delta, and PPARgamma rapidly decreased after cell isolation and remained persistently reduced during the 14-day culture period. Cells progressively increased in size and developed both re-expression of atrial natriuretic factor and downregulation of regulatory proteins of fatty acid metabolism. Supplementation of the medium with fatty acid (oleate 0.25 mM/palmitate 0.25 mM) prevented inactivation of PPARs and downregulation of metabolic genes. Furthermore, cell size and markers of hypertrophy were markedly reduced. Selective activation of either PPARalpha or PPARbeta/delta completely restored expression of regulatory genes of fatty acid metabolism but did not influence cardiac myocyte size and markers of hypertrophy. Conversely, activation of PPARgamma prevented cardiomyocyte hypertrophy but had no effect on fatty acid metabolism. The results indicate that PPAR activity markedly influences hypertrophic transformation of adult rat cardiac myocytes. Inactivation of PPARalpha and PPARbeta/delta accounts for downregulation of the fatty acid oxidation pathway, whereas inactivation of PPARgamma enables development of hypertrophy.
过氧化物酶体增殖物激活受体（PPARs）的α、β/δ和γ亚型的失活介导了成年心肌细胞肥大转化的不同方面。PPARs是配体激活的转录因子，可调节新生儿心肌细胞中脂肪酸代谢的转录调控和肥大反应。本研究的目的是确定PPAR亚型在培养的成年心肌细胞形态和代谢表型转化中的作用，在含有20%胎牛血清的培养基中，成年心肌细胞会经历类似肥大的细胞生长，并伴有脂肪酸代谢调节蛋白的下调。细胞分离后，PPARα、PPARβ/δ和PPARγ的表达和DNA结合活性迅速下降，并在14天的培养期内持续降低。细胞逐渐增大，心房利钠因子重新表达，脂肪酸代谢调节蛋白下调。在培养基中添加脂肪酸（油酸盐0.25 mM/棕榈酸盐0.25 mM）可防止PPARs失活和代谢基因下调。此外，细胞大小和肥大标志物明显降低。选择性激活PPARα或PPARβ/δ可完全恢复脂肪酸代谢调节基因的表达，但不影响心肌细胞大小和肥大标志物。相反，激活PPARγ可防止心肌细胞肥大，但对脂肪酸代谢无影响。结果表明，PPAR活性显著影响成年大鼠心肌细胞的肥大转化。PPARα和PPARβ/δ的失活导致脂肪酸氧化途径下调，而PPARγ的失活则导致肥大的发展。
