Early induction of transforming growth factor-β via angiotensin II type 1 receptors contributes to cardiac fibrosis induced by long-term blockade of nitric oxide synthesis in rats

Hideharu Tomita, Kensuke Egashira, Yuichi Ohara, Masao Takemoto, Masamichi Koyanagi, Makoto Katoh, Hiroaki Yamamoto, Kiyoshi Tamaki, Hiroaki Shimokawa, Akira Takeshita

Research output: Contribution to journalArticle

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Abstract

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-β (TGF-β) is a key molecule that is responsible for tissue fibrosis. The present study investigated the role of TGF-β in the pathogenesis of cardiac fibrosis. The development of cardiac fibrosis by oral administration of the NO synthesis inhibitor N(ω)-nitro-L-arginine methyl ester (L-NAME) to normal rats was preceded by increases in mRNA levels of cardiac TGF-β1 and extracellular matrix (ECM) proteins. TGF-β immunoreactivity was increased in the areas of fibrosis. Treatment with a specific angiotensin II type I receptor antagonist, but not with hydralazine, completely prevented the L-NAME-induced increases in the gene expression of TGF-β1 and ECM proteins and also prevented cardiac fibrosis. Intraperitoneal injection of neutralizing antibody against TGF-β did not affect the L-NAME-induced increase in TGF-β1 mRNA levels but prevented an increase in the mRNA levels of ECM protein. These results suggest that the early induction of TGF-β via the angiotensin II type 1 receptor plays a major role in the development of cardiac fibrosis in this model.

Original languageEnglish
Pages (from-to)273-279
Number of pages7
JournalHypertension
Volume32
Issue number2
DOIs
Publication statusPublished - Aug 1998

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Angiotensin Type 1 Receptor
Transforming Growth Factors
Nitric Oxide
Fibrosis
Extracellular Matrix Proteins
NG-Nitroarginine Methyl Ester
Messenger RNA
Hydralazine
Angiotensin I
Angiotensin Receptor Antagonists
Peptidyl-Dipeptidase A
Neutralizing Antibodies
Intraperitoneal Injections
Oral Administration
Gene Expression

All Science Journal Classification (ASJC) codes

  • Internal Medicine

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Early induction of transforming growth factor-β via angiotensin II type 1 receptors contributes to cardiac fibrosis induced by long-term blockade of nitric oxide synthesis in rats. / Tomita, Hideharu; Egashira, Kensuke; Ohara, Yuichi; Takemoto, Masao; Koyanagi, Masamichi; Katoh, Makoto; Yamamoto, Hiroaki; Tamaki, Kiyoshi; Shimokawa, Hiroaki; Takeshita, Akira.

In: Hypertension, Vol. 32, No. 2, 08.1998, p. 273-279.

Research output: Contribution to journalArticle

Tomita, Hideharu ; Egashira, Kensuke ; Ohara, Yuichi ; Takemoto, Masao ; Koyanagi, Masamichi ; Katoh, Makoto ; Yamamoto, Hiroaki ; Tamaki, Kiyoshi ; Shimokawa, Hiroaki ; Takeshita, Akira. / Early induction of transforming growth factor-β via angiotensin II type 1 receptors contributes to cardiac fibrosis induced by long-term blockade of nitric oxide synthesis in rats. In: Hypertension. 1998 ; Vol. 32, No. 2. pp. 273-279.
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