Stimulation of peroxisome-proliferator-activated receptor alpha (PPAR alpha) attenuates cardiac fibrosis and endothelin-1 production in pressure-overloaded rat hearts.
Endothelin-1 (ET-1) production is increased in hypertrophied hearts accompanied with fibrosis. ET-1 is a potent mitogen of fibroblasts and ET receptor antagonists are reported to inhibit the proliferation of fibroblasts and cardiac fibrosis. Peroxisome-proliferator-activated receptor alpha (PPAR alpha), one of the nuclear hormone receptors, suppresses activator protein-1 (AP-1), one of the nuclear transcription factors. Activation of PPAR alpha is reported to inhibit thrombin-induced ET-1 production by repressing the AP-1 signalling pathway in vascular endothelial cells. We investigated effects of the PPAR alpha activator fenofibrate (80 mg/kg per day, per os) on mRNA levels of ET-1, collagen type I and type III and histological features of myocardial fibrosis in hypertrophied rat hearts due to pressure-overload by abdominal aortic banding (AB). The treatment with fenofibrate or vehicle was started 7 days before the AB operation. Four days after the AB operation, fenofibrate treatment significantly reduced ET-1 mRNA expression compared with vehicle treatment in AB rat hearts. Collagen type I and type III mRNA expression, and interstitial and perivascular fibrosis were attenuated in the fenofibrate-treated AB rat group. Since the ET-1 gene has AP-1 response elements in the 5'-flanking region, it is suggested that myocardial fibrosis is effectively inhibited by fenofibrate through suppression of AP-1-mediated ET-1 gene augmentation in the pressure-overloaded heart caused by aortic banding in rats.
Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan.
Takehiro
T
Ogata
Takashi
T
Miyauchi
Satoshi
S
Sakai
Yoko
Y
Irukayama-Tomobe
Katsutoshi
K
Goto
Iwao
I
Yamaguchi
D000818:Animals; D006332:Cardiomegaly / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D024042:Collagen Type I / Q000235:genetics; D024061:Collagen Type III / Q000235:genetics; D004719:Endomyocardial Fibrosis / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000235:genetics; D011345:Fenofibrate / Q000627:therapeutic use*; D008297:Male; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D024042:Collagen Type I; D024061:Collagen Type III; D019332:Endothelin-1; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D011345:Fenofibrate