Peroxisome proliferator-activated receptor alpha (PPAR alpha) agonist, WY-14,643, increased transcription of myosin light chain-2 in cardiomyocytes.
Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that can be activated by xenobiotics and natural fatty acids. To assess the potential physiological activity of PPAR ligands on cardiac muscular cells, the effects of PPAR alpha agonist, WY-14,643, on both rat hearts and a rat cardiomyocyte cell line (H9c2 cells) were investigated. Male F344 rats were fed a diet containing WY-14,643 at a concentration of 100 ppm for 26 weeks. Cardiac muscular hypertrophy was revealed by morphometric analysis in which the diameter of the muscular fibers in WY-14,643-treated rats was larger than those of control rats. Using H9c2 cells in vitro, the protein content per cell was increased in a dose-dependent manner with the treatment of WY-14,643. The transcription of myosin light chain-2 (MLC-2), a parameter of myocardial hypertrophy, was increased in H9c2 cells transfected with the rat MLC-2/luciferase fusion gene by WY-14,643 as well as other peroxisome proliferators, clofibrate and di(2-ethylhexyl) phthalate. In addition, accumulation of myosin light chain protein was confirmed in H9c2 cells treated with WY-14,643 at 10 micrograms/ml for 7 days or more by immunohistochemistry. These results suggest that PPAR alpha ligands have a potential to regulate MLC-2, which is a contractile protein in cardiomyocytes and may play a part of role in the pathogenesis of cardiac hypertrophy.
Hamano
T
T
Toxicology Laboratory, Mitsubishi Pharma Co., 100-5 Yana, Kisarazu-shi, Chiba 292-0812, Japan.
Kobayashi
K
K
Sakairi
T
T
Hayashi
M
M
Mutai
M
M
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D024722:Cardiac Myosins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002994:Clofibrate / Q000633:toxicity; D004051:Diethylhexyl Phthalate / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects*; D007150:Immunohistochemistry; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018994:Myosin Light Chains / Q000235:genetics* / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D020025:Peroxisome Proliferators / Q000633:toxicity*; D011506:Proteins / Q000032:analysis; D011743:Pyrimidines / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D014157:Transcription Factors / Q000819:agonists*; D014158:Transcription, Genetic / Q000187:drug effects*
D018994:Myosin Light Chains; D020025:Peroxisome Proliferators; D011506:Proteins; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C107184:myosin light chain 2; C006253:pirinixic acid; D004051:Diethylhexyl Phthalate; D024722:Cardiac Myosins; D002994:Clofibrate