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TGF-beta(1) downregulates PTHrP in coronary endothelial cells
S Wenzel1, K Schorr, H Degenhardt
1Physiologisches Institut, Justus-Liebig-Universität Giessen, Germany.
Insights
Transforming growth factor-beta(1) reduces parathyroid hormone-related peptide (PTHrP) expression in cardiac endothelial cells. This finding is relevant for understanding PTHrP
Area of Science:
- Cardiovascular Biology
- Endocrinology
- Molecular Biology
Background:
- Parathyroid hormone-related peptide (PTHrP) is present in the cardiovascular system, particularly in coronary endothelial cells.
- The regulatory factors influencing cardiac PTHrP expression remain largely unexamined.
- Transforming growth factor-beta(1) (TGF-β1) is implicated in various cardiovascular conditions.
Purpose of the Study:
- To investigate the effect of TGF-β1 on ventricular PTHrP expression.
- To explore the relationship between TGF-β1, PTHrP, and cardiac hypertrophy in different physiological and pathophysiological states.
Main Methods:
- Isolation of rat coronary endothelial cells for in vitro analysis.
- Immunoblotting and RT-PCR to quantify PTHrP protein and mRNA levels.
- Studies in transgenic mice overexpressing TGF-β1 and in spontaneously hypertensive rats (SHR-SP).
- Investigation of ventricular PTHrP in a rat model of pressure-induced cardiac hypertrophy (aortic banding).
Main Results:
- TGF-β1 caused a concentration-dependent decrease in PTHrP protein in cultured coronary endothelial cells within 24 hours.
- Transgenic mice overexpressing TGF-β1 exhibited reduced ventricular PTHrP protein and mRNA.
- In aging SHR-SP rats, increased TGF-β1 correlated with downregulated ventricular PTHrP mRNA.
- Pressure-induced cardiac hypertrophy without TGF-β1 induction led to transiently increased ventricular PTHrP.
- PTHrP expression was reduced under all conditions involving TGF-β1 exposure to coronary endothelial cells.
Conclusions:
- TGF-β1 downregulates PTHrP expression in ventricular coronary endothelial cells.
- Cardiac PTHrP expression does not correlate with cardiac hypertrophy.
- The downregulation of PTHrP by TGF-β1 is significant for the paracrine functions of PTHrP in the ventricle.
Abstract:
Parathyroid hormone-related peptide (PTHrP) is expressed throughout the cardiovascular system including coronary endothelial cells. Factors involved in the regulation of cardiac PTHrP expression have not been examined before. This study investigates the influence of transforming growth factor (TGF)-beta(1)on ventricular PTHrP expression. Coronary endothelial cells were isolated from ventricles of adult rats and PTHrP protein expression in these cultures was analysed by immunoblotting. TGF-beta(1)caused a concentration-dependent reduction in PTHrP protein within 24 h. In transgenic mice over-expressing TGF-beta(1)ventricular PTHrP protein expression and release was reduced compared to non-transgenic littermates. Similar concerns hold for PTHrP mRNA content (RT-PCR). Since ventricular TGF-beta(1)expression increases under pathophysiological conditions like arterial hypertension, ventricular PTHrP expression was further determined in aging spontaneously hypertensive (SHR-SP) and normotensive rats. TGF- beta(1)expression was increased in SHR-SP and ventricular PTHrP mRNA expression was downregulated at the age of 10 months. PTHrP expression did not recover in elder SHR-SP in which TGF-beta(1)expression was normalized again. Finally, we investigated ventricular PTHrP expression in rats after banding of the ascending aorta which generates a pressure induced hypertrophy without an induction of TGF-beta(1)expression. In ventricles from these animals, PTHrP expression was transiently increased and normalized at day 3. In conclusion, PTHrP expression was reduced under all conditions in which coronary endothelial cells were exposed to TGF-beta(1). PTHrP expression does not correlate with cardiac hypertrophy. Since coronary endothelial cells represent the majority of PTHrP producing cells in the ventricle its downregulation by TGF- beta(1)seems to be relevant for the paracrine effects of PTHrP.