Early induction of transforming growth factor-beta via angiotensin II type 1 receptors contributes to cardiac fibrosis induced by long-term blockade of nitric oxide synthesis in rats.
We previously reported that the chronic inhibition of nitric oxide (NO) synthesis increases cardiac tissue angiotensin-converting enzyme expression and causes cardiac fibrosis in rats. However, the mechanisms are not known. Transforming growth factor-beta (TGF-beta) is a key molecule that is responsible for tissue fibrosis. The present study investigated the role of TGF-beta in the pathogenesis of cardiac fibrosis. The development of cardiac fibrosis by oral administration of the NO synthesis inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) to normal rats was preceded by increases in mRNA levels of cardiac TGF-beta1 and extracellular matrix (ECM) proteins. TGF-beta immunoreactivity was increased in the areas of fibrosis. Treatment with a specific angiotensin II type 1 receptor antagonist, but not with hydralazine, completely prevented the L-NAME-induced increases in the gene expression of TGF-beta1 and ECM proteins and also prevented cardiac fibrosis. Intraperitoneal injection of neutralizing antibody against TGF-beta did not affect the L-NAME-induced increase in TGF-beta1 mRNA levels but prevented an increase in the mRNA levels of ECM protein. These results suggest that the early induction of TGF-beta1 via the angiotensin II type 1 receptor plays a major role in the development of cardiac fibrosis in this model.
Research Institute of Angiocardiology and the Second Department of Internal Medicine, Kyushu University Faculty of Medicine, Fukuoka, Japan.
H
H
Tomita
K
K
Egashira
Y
Y
Ohara
M
M
Takemoto
M
M
Koyanagi
M
M
Katoh
H
H
Yamamoto
K
K
Tamaki
H
H
Shimokawa
A
A
Takeshita
D000284:Administration, Oral; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004719:Endomyocardial Fibrosis / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D051381:Rats; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000502:physiology*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*
D004791:Enzyme Inhibitors; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D016212:Transforming Growth Factor beta; D009569:Nitric Oxide; D019331:NG-Nitroarginine Methyl Ester