J Korean Pediatr Soc.  2003 Jul;46(7):668-678.

Effects of Endothelin A Receptor Antagonist to Cellular Proliferation and Apoptosis in Neonatal Rat Heart

• Choi BM
• Yoo KH
• Hong YS
• Lee JW
• Kim SK

Abstract

PURPOSE
In order to investigate the role of endothelins in the cardiac development, the present study was designed to examine the effects of endothelin A receptor(ETAR) antagonist to the cellular proliferation and apoptosis in the neonatal rat heart. In addition, the expression of various regulatory genes in protein and mRNA levels by ETAR antagonist were examined.
METHODS
Neonatal Spargue-Dawley rats were separated into two groups. The BMS group(N=22) was treated with the selective ETAR antagonist(Bristo-Myers Squibb-182874; 300 mg/Kg/day) and the control group(N=20) with normal saline for seven days by orogastric tube. On the following day, their hearts were harvested for determination of apoptosis by modified TUNEL technique and cellular proliferation by PCNA stain. In addition to this, Western blottings and RT-PCRs of bcl-x, clusterin, p53 and TGF-beta1 were performed.
RESULTS
The BMS group resulted in a reduced body weight, but not a significantly reduced heart weight. In the BMS group, cardiac apoptotic cells and PCNA positive cells were decreased(P<0.05). In the BMS group, clusterin and bcl-x protein expressions were increased(P<0.05), but p53 and TGF-beta1 protein expressions remained the same. In the BMS group, clusterin and TGF-beta1 mRNA expressions were increased(P<0.05), but bcl-x and p53 mRNA expressions remained the same.
CONCLUSION
ETAR antagonist treatment decreases cell turnover in the developing rat heart, which may account for the role of endothelins on modulating cardiac growth. These changes may be affected by clusterin and bcl-x expressions. These results support that there are some roles of endothelin and ETAR in the cellular level of early neonatal cardiac growth.

Keyword

Endothelin A receptor antagonist; Bristo-Myers Squibb-182874; Cellular proliferation; Apoptosis; Bcl-x; Clusterin; p53; TGF-beta; Developing heart; Rat

MeSH Terms

Animals
Apoptosis*
bcl-X Protein
Blotting, Western
Body Weight
Cell Proliferation*
Clusterin
Endothelins*
Genes, Regulator
Heart*
In Situ Nick-End Labeling
Proliferating Cell Nuclear Antigen
Rats*
Receptor, Endothelin A*
RNA, Messenger
Transforming Growth Factor beta
Transforming Growth Factor beta1
Clusterin
Endothelins
Proliferating Cell Nuclear Antigen
RNA, Messenger
Receptor, Endothelin A
Transforming Growth Factor beta
Transforming Growth Factor beta1
bcl-X Protein