Carbacyclin induces carnitine palmitoyltransferase-1 in cardiomyocytes via peroxisome proliferator-activated receptor (PPAR) delta independent of the IP receptor signaling pathway.
Prostacyclin (PGI2) and its analogues exert cardioprotective effects via the rhodopsin type membrane PGI2 receptor, IP. Peroxisome proliferator-activated receptor (PPAR) delta is a nuclear receptor abundantly expressed in cardiomyocytes and plays a pivotal role in maintaining constitutive mitochondrial fatty acid beta-oxidation (FAO). Recently, a novel signaling pathway of PGI2 via PPARdelta has been demonstrated in non-cardiac tissues. We therefore examined whether carbacyclin (cPGI2), a PGI2 analogue, up-regulates transcriptional expression of carnitine palmitoyltransferase-1 (CPT-1), the rate-limiting enzyme in mitochondrial FAO, via PPARdelta in cardiomyocytes. Intraperitoneal injection of cPGI2 increased CPT-1 mRNA expression in murine hearts. Transcriptional activity was evaluated by PPAR responsive element (PPRE)-luciferase reporter gene assay in cultured neonatal rat cardiomyocytes. CPT-1 mRNA expression and PPRE promoter activity were significantly increased by cPGI2 in a concentration-dependent manner, where PPRE has been mapped to the promoter region of the CPT-1 gene. Moreover, the elevation of CPT-1 mRNA expression and PPRE promoter activity by cPGI2 was not abolished by H-89, a potent protein kinase A inhibitor, but was significantly inhibited in cardiomyocytes over-expressing a dominant-negative type of PPARdelta. Furthermore, electrophoretic mobility shift assays demonstrated that binding of PPARdelta to PPRE in the CPT-1 gene promoter is enhanced in response to cPGI2 stimulation. In addition, down-regulation of CPT-1 mRNA expression in cardiomyocytes subjected to hypoxia was attenuated by cPGI2. These results indicate that cPGI2 induces CPT-1 mRNA expression through PPARdelta, independent of the IP receptor signaling pathway, suggesting a possibility that cPGI2 modulates cardiac energy metabolism by activating FAO via PPARdelta.
Kuroda
Tadashi
T
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Hirota
Hisao
H
Fujio
Yasushi
Y
Sugiyama
Shoko
S
Masaki
Mitsuru
M
Hiramoto
Yoshimune
Y
Shioyama
Wataru
W
Okamoto
Kitaro
K
Hori
Masatsugu
M
Yamauchi-Takihara
Keiko
K
D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004790:Enzyme Induction / Q000187:drug effects; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology; D005786:Gene Expression Regulation; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000201:enzymology*; D047494:PPAR delta / Q000187:drug effects* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D044006:Receptors, Epoprostenol / Q000187:drug effects; D015398:Signal Transduction
D047494:PPAR delta; D012333:RNA, Messenger; D044006:Receptors, Epoprostenol; C026678:carboprostacyclin; D011464:Epoprostenol; D002334:Carnitine O-Palmitoyltransferase