on December 18, 2003
Published online before print December 18, 2003, doi: 10.1161/01.ATV.0000112930.40564.89
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Submitted on September 8, 2003
Accepted on November 19, 2003
Involvement of Apoptosis Signal-Regulating Kinase-1 on Angiotensin II-Induced Monocyte Chemoattractant Protein-1 Expression
Takashi Omura *;
From the Departments of Internal Medicine and Cardiology (T.O., M.Y., R.M., Y.N., Y.I., K.A., K.T., J.Y.), and Pharmacology (S.K., H.I.), Osaka City University Medical School, Osaka, Japan; the Laboratory of Cell Signaling, Graduate School of Pharmaceutical Science (H.I.), University of Tokyo, Japan; and the Antibiotics Laboratory (T.S.), RIKEN, Saitama, Japan
* To whom correspondence should be addressed. E-mail: omura{at}med.osaka-cu.ac.jp.
Objective--Monocyte chemoattractant protein 1 (MCP-1) could contribute to enhanced leukocyte recruitment and activation resulting in chronic tissue damage. However, little is known about the molecular mechanisms of cardiac MCP-1 expression. To elucidate these molecular mechanisms, angiotensin II-induced expression of MCP-1 was examined in cultured rat neonatal ventricular cardiomyocytes and fibroblasts by adenovirus gene transfer.
Methods and Results--MCP-1 mRNA increased 3.6-fold in cardiac fibroblasts at 3 hours after 100 nmol/L angiotensin-II stimulation (P<0.01), whereas MCP-1 mRNA in cardiomyocytes was unchanged. Angiotensin II significantly enhanced JNK, p38MAPK, and nuclear factor-
B (NF-B) activities of cardiac fibroblasts. Wild-type ASK-1 increased MCP-1 expression of cardiac fibroblasts, whereas dominant negative mutant of ASK-1 (DN-ASK), dominant negative mutant of p38MAPK (DN-p38MAPK), and pyrrolidine dithiocarbamate significantly inhibited such expression. The increased MCP-1 mRNA expression in wild-type ASK-1 transfected fibroblasts was inhibited by cotransfection with adenovirus expressing DN-p38MAPK. On the contrary, the decreased MCP-1 mRNA expression in DN-ASK transfected cells was increased by cotransfection with adenovirus expressing constitutively active MKK6.
Conclusion--Angiotensin II induced MCP-1 gene expression in cardiac fibroblasts. The angiotensin II-induced activation of ASK-1 followed by p38MAPK and NF-B signaling in cardiac fibroblasts is partially involved in myocardial MCP-1 expression.
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