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Down‐regulation of BMP‐4 Expression in Coronary Arterial Endothelial Cells: Role of Shear Stress and the cAMP/PKA Pathway
Author(s) -
Csiszar Anna,
Labinskyy Nazar,
Smith Kira E,
Rivera Aracelie,
Bakker Erik N.T.P.,
Jo Hanjoong,
Gardner Jason,
Ungvari Zoltan
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.1145.1
Subject(s) - forskolin , activator (genetics) , medicine , bone morphogenetic protein , endocrinology , chemistry , microbiology and biotechnology , bone morphogenetic protein 2 , gene knockdown , endothelium , signal transduction , biology , gene , stimulation , biochemistry , in vitro
Bone morphogenetic protein 4 (BMP‐4) is a TGFâ family member cytokine that exerts pro‐inflammatory effects on the endothelium. Atheroprotective levels of shear stress (SS) were shown to control endothelial BMP‐4 expression, however, the underlying mechanisms remained unknown. We found that SS down‐regulated expression BMP‐4 (but not BMP‐2, a related cytokine) in coronary arterial endothelial cells (CAECs) as well as in cultured mesenteric arterioles. In HCAECs 8‐Br‐cAMP, the adenylate cyclase activator forskolin or a PKA activator effectively decreased BMP‐4 expression, mimicking the effects of SS. Indeed, SS induced the nuclear translocation of PKA‐c, and inhibition of PKA attenuated the effects of SS and forskolin on BMP‐4 expression. RNA decay assay and BMP‐4 promoter‐driven luciferase reporter gene assay showed that cAMP regulates BMP‐4 expression at the transcriptional level. Thus, laminar SS and cAMP/PKA pathway are important negative regulators of BMP‐4 expression in ECs. Because BMP‐4 elicits endothelial activation and dysfunction, hypertension and vascular calcification, inhibition of BMP‐4 expression by SS and the cAMP/PKA pathway is likely to exert vasculoprotective effects.