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Histamine‐induced Cyclooxygenase‐2 Expression in Human Coronary Artery Endothelial Cells is Mediated Through MAP Kinases
Author(s) -
KRISHNAN HARINIVAS H,
Tan Xiaoyu,
Stechschulte Daniel J,
Dileepan Kottarappat N
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1052.5
Subject(s) - p38 mitogen activated protein kinases , histamine , kinase , phosphorylation , mapk/erk pathway , mitogen activated protein kinase , cyclooxygenase , microbiology and biotechnology , prostacyclin , chemistry , biology , pharmacology , endocrinology , biochemistry , enzyme
Previous studies from our laboratory showed that treatment of human coronary artery endothelial cells (HCAEC) with histamine led to overexpression of cyclooxygenase‐2 (COX‐2) gene and protein (but not COX‐1), and increased production of its products PGE 2 and PGI 2 (Tan et al, J.Immunol, 179: 7899–7906, 2007). In this study, we investigated the involvement of MAP kinases in the signaling mechanisms leading to the histamine‐mediated COX‐2 overexpression in HCAEC. Treatment of HCAEC with histamine (10μg/ml) resulted in multi‐fold increases in the phosphorylation of p38 MAPK, ERK and JNK. Histamine‐induced phosphorylation of these proteins continued for 10–15 minutes post treatment, after which the phosphorylation levels returned to the basal levels. Incubation of HCAEC with pharmacological inhibitors of the individual MAP Kinases inhibited histamine‐induced COX‐2 gene expression as quantified by real time PCR. The inhibitors also abrogated phosphorylation of specific MAP Kinases confirming the involvement of MAP Kinase pathway in COX‐2 overexpression. In addition, inhibition of the MAP Kinases also inhibited HCAEC generation of prostacyclin (PGI 2 ) confirming that histamine mediated phosphorylation of MAP Kinases is involved in the PGI 2 production in HCAEC. These results indicate that histamine‐mediated overexpression of COX‐2 and the resultant production of PGI 2 require p38, ERK, and JNK activation, and inhibition of any of these MAP kinases can decrease the expression of COX‐2 and the production of PGI 2 . (Supported by NIH R01‐HL070101 and Carey Arthritis Fund)