Liang Faquan, Wang Feng, Zhang Sumei, Gardner David G
Diabetes Center, University of California at San Francisco, San Francisco, California 94143-0540, USA.
Endocrinology. 2003 Sep;144(9):4187-94. doi: 10.1210/en.2002-0217.
The peroxisome proliferator activated receptors (PPARs) appear to have beneficial effects in the cardiovascular system. PPAR gamma has been shown previously to exert an inhibitory effect on cardiac myocyte hypertrophy in vivo and in vitro. Using endothelin to activate the hypertrophic program in neonatal rat cardiac myocytes, we demonstrate that PPAR alpha ligands (fenofibrate and WY14,643) suppress hypertrophy-dependent increases in protein synthesis, cell surface area, and sarcomeric organization in vitro. This was accompanied by a decrease in brain natriuretic peptide gene expression, a marker of transcriptional activation in hypertrophy. These effects were equivalent to or greater than those seen with the PPAR gamma agonist rosiglitazone. Fenofibrate and rosiglitazone suppressed endothelin stimulation of human brain natriuretic peptide gene promoter activity, and this effect was amplified by cotransfection of PPAR alpha and PPAR gamma expression vectors, respectively. The fenofibrate-dependent suppression of endothelin's stimulatory activity was dependent upon promoter sequence positioned between -904 and -40 relative to the transcription start site and did not appear to involve a number of positive and negative regulatory elements that are known to govern transcription of this gene. These findings suggest that PPAR alpha ligands could prove to be useful in the management of disorders associated with hypertrophy and remodeling of the myocardium.
过氧化物酶体增殖物激活受体（PPARs）似乎在心血管系统中具有有益作用。先前已表明PPARγ在体内和体外对心肌细胞肥大均有抑制作用。利用内皮素激活新生大鼠心肌细胞中的肥大程序，我们证明PPARα配体（非诺贝特和WY14,643）在体外可抑制肥大相关的蛋白质合成增加、细胞表面积增加和肌节组织变化。这伴随着脑钠肽基因表达的降低，脑钠肽是肥大中转录激活的标志物。这些作用等同于或大于PPARγ激动剂罗格列酮的作用。非诺贝特和罗格列酮抑制内皮素对人脑钠肽基因启动子活性的刺激，并且分别通过共转染PPARα和PPARγ表达载体增强了这种作用。非诺贝特对内皮素刺激活性的抑制作用取决于相对于转录起始位点位于-904至-40之间的启动子序列，并且似乎不涉及已知调控该基因转录的许多正负调控元件。这些发现表明，PPARα配体可能被证明对治疗与心肌肥大和重塑相关的疾病有用。
