Activation of peroxisome proliferator-activated receptor α in megakaryocytes reduces platelet-derived growth factor-BB in platelets.
OBJECTIVE
Platelet-derived growth factor (PDGF)-BB plays a crucial role in atherosclerosis and vascular remodeling by promoting the migration and proliferation of vascular smooth muscle cells. The objective of this study was to clarify the pleiotropic effect of peroxisome proliferator-activated receptor α (PPARα) activators on PDGF-BB expression in megakaryocytes and platelets.


RESULTS
The expression of PPARα in a human erythroleukemia (HEL) cells was clearly detected by reverse transcriptase-PCR and immunofluorescence microscopy. The expression level of PPARα in HEL cells was unchanged regardless of differentiation into megakaryocytic cells by treatment with phorbol 12-myristate 13 acetate (TPA). The TPA-induced expression of PDGF-B mRNA and PDGF-BB protein levels in culture media was significantly decreased by treatment with PPARα activators, Wy14643 and fenofibric acid, in a dose-dependent manner. PDGF-BB expression induced by inflammatory cytokines, including interleukin-1β or interleukin-6, was also significantly suppressed by treatment with PPARα activators. Immunohistochemistry of human bone marrow showed the expression of PPARα in both the nucleus and cytoplasm of megakaryocytes. In addition, PDGF-BB levels in platelets were significantly decreased from 1,800±870 to 1,470±840 pg/10(5) platelets (mean±SD, p<0.05) by treatment with 300 mg fenofibrate once daily for 4 weeks in 13 patients with dyslipidemia.


CONCLUSIONS
Activation of PPARα in megakaryocytes reduces PDGF-BB expression in platelets. PPARα activators may exert vasculo-protective action through suppression of PDGF-BB production in a megakaryocyte/platelet pathway.
Department of Medicine and Bioregulatory Sciences, The University of Tokushima Graduate School of Health Biosciences, Tokushima, Japan.
Shunji
S
Hashizume
Masashi
M
Akaike
Hiroyuki
H
Azuma
Kazue
K
Ishikawa
Sumiko
S
Yoshida
Yuka
Y
Sumitomo-Ueda
Shusuke
S
Yagi
Yasumasa
Y
Ikeda
Takashi
T
Iwase
Ken-ichi
K
Aihara
Masahiro
M
Abe
Masataka
M
Sata
Toshio
T
Matsumoto
D000328:Adult; D000077214:Becaplermin; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D050171:Dyslipidemias / Q000097:blood / Q000188:drug therapy; D005260:Female; D011345:Fenofibrate / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008055:Lipids / Q000097:blood; D008297:Male; D008533:Megakaryocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008875:Middle Aged; D047493:PPAR alpha / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D008055:Lipids; D047493:PPAR alpha; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; D012333:RNA, Messenger; D000077214:Becaplermin; C006253:pirinixic acid; D013755:Tetradecanoylphorbol Acetate; D011345:Fenofibrate