Transforming growth factor beta 1 and extracellular matrix gene expression in isoprenaline induced cardiac hypertrophy: effects of inhibition of the renin-angiotensin system.
OBJECTIVE
The aim was to investigate changes in cardiac transforming growth factor beta 1 (TGF-beta 1), fibronectin, and collagen types I and III mRNA levels in isoprenaline induced cardiac hypertrophy, and the effects of delapril, an angiotensin converting enzyme inhibitor, and TCV-116, an angiotensin II type 1 receptor antagonist, on this hypertrophy.


METHODS
Rats were continuously infused with saline and low or high dose of isoprenaline (0.5 or 3 mg.kg-1.d-1) by an osmotic minipump for 24 h, 48 h or 7 d. Treatment with delapril (100 mg.kg-1.d-1) or TCV-116 (10 mg.kg-1.d-1) was started from 1 d before the implantation of minipump to the end of experiments. After the experimental periods, left ventricular weight was measured and the mRNA was extracted and measured by northern blot hybridisation.


RESULTS
Both low and high doses of isoprenaline infusion resulted in increased left ventricular weight. With low dose infusion, cardiac TGF-beta 1 mRNA was not stimulated throughout the infusion, while fibronectin mRNA and collagen types I and III mRNAs began to increase at 24 h and 48 h, respectively, after the infusion. In high dose isoprenaline infusion, not only was extracellular matrix mRNA but also TGF-beta 1 mRNA in the ventricle significantly increased. TCV-116 prevented isoprenaline induced left ventricular hypertrophy as much as delapril. However, with delapril or TCV-116, the time course of TGF-beta 1 and ECM mRNA expression was almost similar to isoprenaline infusion only.


CONCLUSIONS
The extracellular matrix mRNA expressions are enhanced in myocardial hypertrophy by a low dose of isoprenaline, which is probably not mediated by TGF-beta 1. The preventive effects of TCV-116 on this hypertrophy indicate that the inhibitory effects of angiotensin converting enzyme inhibitor on cardiac hypertrophy are due to the inhibition of angiotensin II and that angiotensin II type I receptor plays an important role in isoprenaline induced left ventricular hypertrophy. However, the renin-angiotensin system may play a minor role in isoprenaline induced cardiac fibrosis.
Omura
T
T
First Department of Internal Medicine, Osaka City University Medical School, Japan.
Kim
S
S
Takeuchi
K
K
Iwao
H
H
Takeda
T
T
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D015152:Blotting, Northern; D006332:Cardiomegaly / Q000378:metabolism*; D003094:Collagen / Q000235:genetics; D005109:Extracellular Matrix / Q000378:metabolism*; D005353:Fibronectins / Q000235:genetics; D015870:Gene Expression; D007189:Indans / Q000494:pharmacology; D007545:Isoproterenol; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D011945:Receptors, Angiotensin; D012084:Renin-Angiotensin System / Q000502:physiology*; D013777:Tetrazoles; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D005353:Fibronectins; D007189:Indans; D012333:RNA, Messenger; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D016212:Transforming Growth Factor beta; D003094:Collagen; D007545:Isoproterenol; C077793:candesartan cilexetil; C047759:delapril