Interaction of the renin-angiotensin system and the endothelin system in cardiac hypertrophy.
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.
Stula
M
M
Benjamin Franklin Hospital, Free University of Berlin, Germany.
Pinto
Y M
YM
Gschwend
S
S
Teisman
A C
AC
van Gilst
W H
WH
Böhm
M
M
Dietz
R
R
Paul
M
M
D000818:Animals; D030801:Animals, Genetically Modified; D016282:Aspartic Acid Endopeptidases / Q000096:biosynthesis / Q000235:genetics; D001794:Blood Pressure / Q000502:physiology; D015152:Blotting, Northern; D006332:Cardiomegaly / Q000235:genetics / Q000503:physiopathology*; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008297:Male; D008666:Metalloendopeptidases; D051379:Mice; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000096:biosynthesis* / Q000235:genetics; D012084:Renin-Angiotensin System / Q000235:genetics / Q000502:physiology*
D016232:Endothelins; D012333:RNA, Messenger; D016282:Aspartic Acid Endopeptidases; D012083:Renin; D008666:Metalloendopeptidases; C000606925:Ece1 protein, mouse; D000072396:Endothelin-Converting Enzymes