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Endothelin-1 and its binding sites are upregulated in pressure overload cardiac hypertrophy
1Second Department of Internal Medicine, Gunma University School of Medicine, Japan.
Insights
This study found that increased endothelin-1 (ET-1) and its receptors in the heart are linked to cardiac hypertrophy in rats subjected to pressure overload. Local ET-1 production by heart cells appears crucial for this condition.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Renal Physiology
Background:
- Cardiac hypertrophy is a significant risk factor for heart failure.
- Endothelin-1 (ET-1) is a potent vasoconstrictor peptide implicated in cardiovascular diseases.
Purpose of the Study:
- To investigate the role of endothelin and its receptors in pressure overload-induced cardiac hypertrophy in vivo.
- To determine the cellular source and temporal changes of ET-1 during cardiac remodeling.
Main Methods:
- Created cardiac hypertrophy in rats via suprarenal abdominal aorta constriction.
- Measured hemodynamic parameters, plasma and ventricular ET-1 levels, and ET-1 binding site density.
- Utilized in situ mRNA hybridization to detect preproendothelin-1 (preproET-1) mRNA expression in cardiac tissue.
Main Results:
- Ventricular ET-1 levels significantly increased by day 8 post-operation, correlating with hypertrophy severity.
- Cardiac myocytes were identified as expressing preproET-1 mRNA in hypertrophied hearts.
- Increased ET-1 binding site density was observed on day 8 without changes in binding affinity.
Conclusions:
- Elevated local endothelin-1 production and increased endothelin receptor density are closely associated with the development of cardiac hypertrophy under pressure overload.
- These findings support the hypothesis that the endothelin system plays a critical role in the pathogenesis of cardiac hypertrophy.
Abstract:
The purpose of this study was to determine whether endothelin and endothelin receptors play an important role in the development of cardiac hypertrophy due to pressure overload in vivo. Cardiac hypertrophy was produced by placing a constricting clip around the suprarenal abdominal aorta of rats. Hemodynamic parameters and plasma and ventricular concentrations of endothelin-1 (ET-1) were measured in control unoperated rats, and 30 min, 2 and 6 h, and 1 and 8 days after operation in pressure overload rats and sham-operated rats. The density and dissociation constant of ET-1 binding sites were also measured in control rats and 1 and 8 days after pressure overload and sham operation. Additionally, in situ mRNA hybridization for preproendothelin-1 (preproET-1) mRNA was performed to determine which cells were responsible for increased ET-1 levels. Ventricular ET-1 levels increased markedly on day 8 of pressure overload, whereas plasma ET-1 levels increased transiently only 30 min after operation, quickly returning to control level. In addition, ventricular ET-1 levels on day 8 showed a significant positive correlation with the degree of cardiac hypertrophy. In situ mRNA hybridization revealed that cardiac myocytes expressed preproET-1 mRNA in hypertrophied hearts in vivo. In accord with the elevation of ventricular ET-1 levels, the density of ET-1 binding sites was increased significantly, without affecting their binding affinity, on day 8 of pressure overload. These data are compatible with the hypothesis that increases in locally produced ET-1 and the density of ET-1 binding sites have an important relationship with the development of cardiac hypertrophy in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)