Peroxisome proliferator-activated receptor-gamma activators inhibit endothelin-1-related cardiac hypertrophy in rats.
Endothelin-1 (ET-1) causes cardiac hypertrophy, and ET receptor antagonists inhibit the development of cardiac hypertrophy in vitro and in vivo. Peroxisome proliferator-activated receptor gamma (PPAR gamma), a member of the family of nuclear receptors, suppresses activator protein-1 (AP-1). We investigated the effects of the thiazolidinediones troglitazone and pioglitazone, activators of PPAR gamma, on cardiac hypertrophy due to pressure overload provoked by abdominal aortic banding (AB) in rats. Rats were divided into four groups: sham operation with vehicle treatment (n=5); AB surgery with vehicle treatment (n=6); AB surgery with troglitazone treatment (100 mg x kg(-1) x day(-1); n=5); and AB surgery with pioglitazone treatment (10 mg x kg(-1) x day(-1); n=8). Treatments were started 7 days before AB surgery, and left ventricular (LV) hypertrophy was assessed 24 h after surgery. The ratio of LV weight/body weight (BW) was significantly increased in AB rats compared with sham-operated rats; treatment of AB rats with troglitazone or pioglitazone significantly inhibited the increase in LV weight/BW. Expression of ET-1 mRNA was markedly enhanced in the left ventricles of AB rats; treatment with troglitazone or pioglitazone lowered expression significantly. Suppression of cardiac hypertrophy by pioglitazone treatment was accompanied by a decrease in expression of the gene encoding brain natriuretic factor, a molecular marker for cardiac hypertrophy, in AB rats. Because the ET-1 gene has AP-1 response elements in its 5'-flanking region, the thiazolidinediones troglitazone and pioglitazone may inhibit cardiac hypertrophy partly through suppression of AP-1-induced ET-1 gene up-regulation.
Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan. ssakai@md.tsukuba.ac.jp
Satoshi
S
Sakai
Takashi
T
Miyauchi
Yoko
Y
Irukayama-Tomobe
Takehiro
T
Ogata
Katsutoshi
K
Goto
Iwao
I
Yamaguchi
D000704:Analysis of Variance; D000818:Animals; D006332:Cardiomegaly / Q000188:drug therapy / Q000378:metabolism*; D002839:Chromans / Q000494:pharmacology*; D019332:Endothelin-1 / Q000378:metabolism*; D016232:Endothelins / Q000235:genetics; D008297:Male; D020097:Natriuretic Peptide, Brain / Q000235:genetics; D000077205:Pioglitazone; D011498:Protein Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013268:Stimulation, Chemical; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000378:metabolism*; D000077288:Troglitazone
D002839:Chromans; D019332:Endothelin-1; D016232:Endothelins; D011498:Protein Precursors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D020097:Natriuretic Peptide, Brain; D000077288:Troglitazone; D000077205:Pioglitazone