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Interaction of the renin-angiotensin system and the endothelin system in cardiac hypertrophy
M Stula1, Y M Pinto, S Gschwend
1Benjamin Franklin Hospital, Free University of Berlin, Germany.
Abstract:
It has been suggested that the renin-angiotensin system (RAS) interacts with the endothelin system in the pathogenesis of cardiac remodeling. We examined endothelin system regulation in a model of chronic RAS dysfunction, which is believed to be an important factor in cardiac remodeling. We used the transgenic rat line TGR(mRen2)27, which overexpresses the mouse Renin-2 gene and shows hypertension and left ventricular hypertrophy compared to Sprague-Dawley (SD) rats. Ren-2 rats (n = 24) received either losartan (LOS), quniapril (QIN), or carvedilol (CARV) for 11 weeks, or no treatment. After 11 weeks left (LV) and right ventricular (RV) weights were determined and total RNA extracted. Ren-2 rats showed a mean systolic blood pressure of 190 mm (+/- SEM), which could be normalized to 110 +/- mm (+/- SEM) by treatment with LOS or QIN. CARV also reduced blood pressure but did not normalize it. LV end-diastolic pressure was normal in both SD and Ren-2 rats. LV weight was increased in the Ren-2 rats compared to SD rats, and was significantly reduced to normal in the LOS and QIN but not in the CARV group. RV weight was normal in all groups. Northern blot analysis of preproendothelin-1 (preproET-1) and endothelin-converting enzyme-1 (ECE-1) expression revealed a significant (p < 0.05) 20% decrease in preproET-1 mRNA in the mRen2 rats in the RV and in the LV, compared to SD rats. ECE-1 mRNA was unchanged. Treatment with LOS, but not with QIN or CARV, induced preproET-1 transcription by threefold (p < 0.01) over baseline in both the LV and RV. ECE-1 mRNA was unaltered in the CARV and LOS group and was decreased by 20% in the QIN group. Similar changes in LV and RV indicated a direct influence of a dysregulated RAS on the endothelin system. In conclusion, the activated RAS downregulates the endothelin system in this model of cardiac hypertrophy. This suggests that in chronic RAS activated, the endothelin system may have a different pathophysiologic impact as a co-factor leading to cardiac hypertrophy.
Insights
Activated renin-angiotensin system (RAS) downregulates the endothelin system in cardiac hypertrophy. Losartan treatment normalized blood pressure and cardiac hypertrophy, suggesting a complex interaction in cardiovascular disease.
Area of Science:
- Cardiovascular Physiology
- Molecular Biology
- Pharmacology
Background:
- The renin-angiotensin system (RAS) and endothelin system are implicated in cardiac remodeling.
- Chronic RAS dysfunction is a key factor in the pathogenesis of cardiac hypertrophy.
Purpose of the Study:
- To investigate the regulation of the endothelin system in a model of chronic RAS dysfunction.
- To examine the effects of RAS-inhibiting drugs on cardiac remodeling and endothelin system expression.
Main Methods:
- Utilized transgenic rats overexpressing the mouse Renin-2 gene (TGR(mRen2)27) exhibiting hypertension and left ventricular hypertrophy.
- Administered losartan, quniapril, or carvedilol for 11 weeks to assess their impact on blood pressure, cardiac weights, and gene expression.
- Analyzed preproendothelin-1 (preproET-1) and endothelin-converting enzyme-1 (ECE-1) mRNA levels via Northern blot.
Main Results:
- Ren-2 rats displayed significant hypertension and left ventricular hypertrophy, which were normalized by losartan and quniapril but not carvedilol.
- PreproET-1 mRNA levels were decreased in the ventricles of Ren-2 rats compared to controls.
- Losartan treatment significantly increased preproET-1 transcription, while quniapril decreased ECE-1 mRNA, indicating differential effects on the endothelin system.
Conclusions:
- Chronic RAS activation downregulates the endothelin system in this model of cardiac hypertrophy.
- The interaction between RAS and the endothelin system is complex and may differ in chronic conditions.
- Targeting the RAS, particularly with agents like losartan, can modulate the endothelin system and impact cardiac remodeling.