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MAP kinase kinase 6-p38 MAP kinase signaling cascade regulates cyclooxygenase-2 expression in cardiac myocytes in vitro and in vivo.
Circ Res. 2003 Apr 18; 92(7):757-64.CircR

Abstract

Cyclooxygenase-2 (COX-2) catalyzes the rate-limiting step in delayed prostaglandin biosynthesis. The purpose of this study was to evaluate the role of the MAP kinase kinase 6 (MKK6)-p38 MAPK signaling cascade in the regulation of myocardial COX-2 gene expression, in vitro and in vivo. RT-PCR analysis identified p38alpha and p38beta2 MAPK mRNA in rat cardiac myocytes. Interleukin-1beta induced the phosphorylation of p38alpha and p38beta2 MAPK in cardiomyocytes and stimulated RNA polymerase II binding to the COX-2 promoter, COX-2 transcription, COX-2 protein synthesis, and prostaglandin E2 (PGE2) release. Infecting cardiomyocytes with adenoviruses that encode mutant, phosphorylation-resistant MKK6 or p38beta2 MAPK inhibited interleukin-1beta-induced p38 MAPK activation, COX-2 gene expression, and PGE2 release. Treatment with the p38alpha and p38beta2 MAPK inhibitor, SB202190, attenuated interleukin-1beta-induced COX-2 transcription and accelerated the degradation of COX-2 mRNA. Cells infected with adenoviruses encoding wild-type or constitutively activated MKK6 or p38beta2 MAPK, in the absence of interleukin-1beta, exhibited increased cellular p38 MAPK activity, COX-2 mRNA expression, and COX-2 protein synthesis, which was blocked by SB202190. In addition, elevated levels of COX-2 protein were identified in the hearts of transgenic mice with cardiac-restricted expression of wild-type or constitutively activated MKK6, in comparison with nontransgenic littermates. These results provide direct evidence that MKK6 mediated p38 MAPK activation is necessary for interleukin-1beta-induced cardiac myocyte COX-2 gene expression and PGE2 biosynthesis in vitro and is sufficient for COX-2 gene expression by cardiac myocytes in vitro and in vivo.

Authors+Show Affiliations

Division of Vascular Surgery, 200 Elizabeth St, EC5-302a, Toronto General Hospital, Toronto, Ontario, Canada M5G-2C4.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12649265

Citation

Degousee, Norbert, et al. "MAP Kinase Kinase 6-p38 MAP Kinase Signaling Cascade Regulates Cyclooxygenase-2 Expression in Cardiac Myocytes in Vitro and in Vivo." Circulation Research, vol. 92, no. 7, 2003, pp. 757-64.
Degousee N, Martindale J, Stefanski E, et al. MAP kinase kinase 6-p38 MAP kinase signaling cascade regulates cyclooxygenase-2 expression in cardiac myocytes in vitro and in vivo. Circ Res. 2003;92(7):757-64.
Degousee, N., Martindale, J., Stefanski, E., Cieslak, M., Lindsay, T. F., Fish, J. E., Marsden, P. A., Thuerauf, D. J., Glembotski, C. C., & Rubin, B. B. (2003). MAP kinase kinase 6-p38 MAP kinase signaling cascade regulates cyclooxygenase-2 expression in cardiac myocytes in vitro and in vivo. Circulation Research, 92(7), 757-64.
Degousee N, et al. MAP Kinase Kinase 6-p38 MAP Kinase Signaling Cascade Regulates Cyclooxygenase-2 Expression in Cardiac Myocytes in Vitro and in Vivo. Circ Res. 2003 Apr 18;92(7):757-64. PubMed PMID: 12649265.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - MAP kinase kinase 6-p38 MAP kinase signaling cascade regulates cyclooxygenase-2 expression in cardiac myocytes in vitro and in vivo. AU - Degousee,Norbert, AU - Martindale,Joshua, AU - Stefanski,Eva, AU - Cieslak,Martin, AU - Lindsay,Thomas F, AU - Fish,Jason E, AU - Marsden,Philip A, AU - Thuerauf,Donna J, AU - Glembotski,Christopher C, AU - Rubin,Barry B, Y1 - 2003/03/20/ PY - 2003/3/22/pubmed PY - 2003/4/26/medline PY - 2003/3/22/entrez SP - 757 EP - 64 JF - Circulation research JO - Circ. Res. VL - 92 IS - 7 N2 - Cyclooxygenase-2 (COX-2) catalyzes the rate-limiting step in delayed prostaglandin biosynthesis. The purpose of this study was to evaluate the role of the MAP kinase kinase 6 (MKK6)-p38 MAPK signaling cascade in the regulation of myocardial COX-2 gene expression, in vitro and in vivo. RT-PCR analysis identified p38alpha and p38beta2 MAPK mRNA in rat cardiac myocytes. Interleukin-1beta induced the phosphorylation of p38alpha and p38beta2 MAPK in cardiomyocytes and stimulated RNA polymerase II binding to the COX-2 promoter, COX-2 transcription, COX-2 protein synthesis, and prostaglandin E2 (PGE2) release. Infecting cardiomyocytes with adenoviruses that encode mutant, phosphorylation-resistant MKK6 or p38beta2 MAPK inhibited interleukin-1beta-induced p38 MAPK activation, COX-2 gene expression, and PGE2 release. Treatment with the p38alpha and p38beta2 MAPK inhibitor, SB202190, attenuated interleukin-1beta-induced COX-2 transcription and accelerated the degradation of COX-2 mRNA. Cells infected with adenoviruses encoding wild-type or constitutively activated MKK6 or p38beta2 MAPK, in the absence of interleukin-1beta, exhibited increased cellular p38 MAPK activity, COX-2 mRNA expression, and COX-2 protein synthesis, which was blocked by SB202190. In addition, elevated levels of COX-2 protein were identified in the hearts of transgenic mice with cardiac-restricted expression of wild-type or constitutively activated MKK6, in comparison with nontransgenic littermates. These results provide direct evidence that MKK6 mediated p38 MAPK activation is necessary for interleukin-1beta-induced cardiac myocyte COX-2 gene expression and PGE2 biosynthesis in vitro and is sufficient for COX-2 gene expression by cardiac myocytes in vitro and in vivo. SN - 1524-4571 UR - https://www.unboundmedicine.com/medline/citation/12649265/MAP_kinase_kinase_6_p38_MAP_kinase_signaling_cascade_regulates_cyclooxygenase_2_expression_in_cardiac_myocytes_in_vitro_and_in_vivo_ L2 - http://www.ahajournals.org/doi/full/10.1161/01.RES.0000067929.01404.03?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -