Activation of the cardiac endothelin system in left ventricular hypertrophy before onset of heart failure in TG(mREN2)27 rats.
OBJECTIVE
To characterize the cardiac angiotensin and endothelin (ET) system in compensated left ventricular hypertrophy due to long standing arterial hypertension and to assess the role of angiotensin and ET converting enzymes in mediating the observed changes of angiotensin and ET levels, respectively.


METHODS
We studied the left ventricular renin-angiotensin system (RAS) and ET system in 20-week-old male transgenic hypertensive TG(mREN2)27 rats, a model of the monogenic renin-dependent form of severe hypertension. Age-matched Sprague-Dawley rats served as controls.


RESULTS
TG(mREN2)27 rats exhibited left ventricular hypertrophy without signs of congestion. Transgene overexpression led to an activation of the tissue RAS with increased angiotensin II levels in spite of unchanged angiotensin converting enzyme (ACE) activity and ACE mRNA levels. ET-1 production was markedly increased in TG(mREN2)27 rats indicating that the ET-system was activated. Cardiac ET-1 in TG(mREN2)27 originated most likely from increased preproET-1 production because preproET-1 mRNA levels were increased but ET converting enzyme gene expression and activity were unchanged. Furthermore, ET-1 binding sites were significantly increased in TG(mREN2)27 rats without changes in K(D) values and ET(A)/ET(B) receptor ratios. ET(A) receptor gene expression was not altered whereas ET(B) receptor mRNA levels were up-regulated twofold in TG(mREN2)27 rats suggesting that ET(A) and ET(B) receptor expression may be regulated differentially.


CONCLUSIONS
Cardiac ET and angiotensin systems are co-activated in compensated cardiac hypertrophy before onset of heart failure, and thus may be involved in the mechanism by which cardiac remodelling and progression of left ventricular dysfunction occur in TG(mREN2)27 rats.
Zolk
Oliver
O
Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstr. 17, 91054 Erlangen, Germany. zolk@pharmakologie.uni-erlangen.de
Quattek
Jessika
J
Seeland
Ute
U
El-Armouche
Ali
A
Eschenhagen
Thomas
T
Böhm
Michael
M
D000804:Angiotensin II / Q000032:analysis / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D016282:Aspartic Acid Endopeptidases / Q000032:analysis / Q000235:genetics; D003094:Collagen / Q000032:analysis; D019332:Endothelin-1 / Q000032:analysis / Q000378:metabolism*; D000072396:Endothelin-Converting Enzymes; D006973:Hypertension / Q000378:metabolism*; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D008666:Metalloendopeptidases; D023421:Models, Animal; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D012083:Renin / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D019332:Endothelin-1; D012333:RNA, Messenger; D017466:Receptors, Endothelin; D000804:Angiotensin II; D003094:Collagen; D007703:Peptidyl-Dipeptidase A; D016282:Aspartic Acid Endopeptidases; D012083:Renin; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes