Angiotensin II enhances interleukin-1 beta-induced MMP-9 secretion in adult rat cardiac fibroblasts.
Cardiac fibroblasts play important roles during the cardiac remodeling through the secretion of matrix metalloproteinase (MMP)-9. Inflammatory cytokine, interleukin (IL)-1beta induces MMP-9 secretion in cultured cardiac fibroblasts. Angiotensin II is well known to play pivotal roles in cardiac remodeling, but the effect of angiotensin II on MMP-9 secretion in cardiac fibroblasts has not been fully clarified. In the present study, we investigated the effect of angiotensin II on basal and IL-1beta-induced MMP-9 secretion in adult rat cardiac fibroblasts. MMP-9 protein secreted into culture medium, and phosphorylation of nuclear factor (NF)-kappaB, c-Jun NH(2)-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) in cell lysates were measured by Western blotting. Angiotensin II (1 nM, 24 hr) alone-treatment did not induce MMP-9 secretion. However, angiotensin II significantly enhanced IL-1beta (4 ng/ml, 24 hr)-induced MMP-9 secretion. Telmisartan (10 nM), an angiotensin II type 1 receptor (AT1R) antagonist, significantly suppressed the enhancement of IL-1beta-induced MMP-9 secretion by angiotensin II, whereas PD123319 (10 nM), an angiotensin II type 2 receptor antagonist, was ineffective. IL-1beta (4 ng/ml, 10 min) induced phosphorylation of NF-kappaB, JNK, and ERK. Angiotensin II augmented the IL-1beta-induced phosphorylation of ERK but not NF-kappaB and JNK. PD98059 (50 microM), a selective inhibitor of ERK pathway, inhibited the angiotensin II enhancement of IL-1beta-induced MMP-9 secretion. These results suggest that angiotensin II enhances IL-1beta-induced MMP-9 secretion through the augmentation of ERK phosphorylation via AT1R in adult rat cardiac fibroblasts.
Department of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Higashi, Towada, Aomori, Japan. mokada@vmas.kitasato-u.ac.jp
Muneyoshi
M
Okada
Hideyuki
H
Yamawaki
Yukio
Y
Hara
D000804:Angiotensin II / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D006321:Heart / Q000187:drug effects; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology*; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D009206:Myocardium / Q000201:enzymology*; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D000077333:Telmisartan
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D053583:Interleukin-1beta; D011994:Recombinant Proteins; D000804:Angiotensin II; D048049:Extracellular Signal-Regulated MAP Kinases; D020781:Matrix Metalloproteinase 1; D000077333:Telmisartan