Peroxisome proliferator activated receptor (PPAR)alpha agonists inhibit hypertrophy of neonatal rat cardiac myocytes.
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.
Liang
Faquan
F
Diabetes Center, University of California at San Francisco, San Francisco, California 94143-0540, USA.
Wang
Feng
F
Zhang
Sumei
S
Gardner
David G
DG
D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D011345:Fenofibrate / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006352:Heart Ventricles / Q000166:cytology; D006984:Hypertrophy; D007004:Hypoglycemic Agents / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000494:pharmacology; D008024:Ligands; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D020097:Natriuretic Peptide, Brain / Q000235:genetics; D020025:Peroxisome Proliferators / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism*; D000077154:Rosiglitazone; D012518:Sarcomeres / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists* / Q000378:metabolism*
D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D008024:Ligands; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; D020097:Natriuretic Peptide, Brain; C006253:pirinixic acid; D011345:Fenofibrate