Journal
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Volume 290, Issue 5, Pages H1740-H1746Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00904.2005
Keywords
EP receptor; cardiac myocytes; hypertrophy; signaling pathways
Funding
- NHLBI NIH HHS [P01-HL-28982] Funding Source: Medline
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Brain natriuretic peptide (BNP) produced by cardiac myocytes has antifibrotic and antigrowth properties and is a marker of cardiac hypertrophy. We previously showed that prostaglandin E-2 (PGE(2)) is the main prostaglandin produced in myocytes treated with proinflammatory stimuli and stimulates protein synthesis by binding to its EP4 receptor. We hypothesized that PGE(2), acting through EP4, also regulates BNP gene expression. We transfected neonatal ventricular myocytes with a plasmid encoding the human BNP (hBNP) promoter driving expression of a luciferase reporter gene. PGE(2) increased hBNP promoter activity 3.5-fold. An EP4 antagonist reduced the stimulatory effect of PGE(2) but not an EP1 antagonist. Because EP4 signaling can involve adenylate cyclase, cAMP, and protein kinase A (PKA), we tested the effect of H-89, a PKA inhibitor, on PGE(2) stimulation of the hBNP promoter. H-89 at 5 mu M decreased PGE(2) stimulation of BNP promoter activity by 100%. Because p42/44 MAPK mediates the effect of PGE(2) on protein synthesis, we also examined the role of MAPKs in the regulation of BNP promoter activity. PGE(2) stimulation of the hBNP promoter was inhibited by a MEK1/2 inhibitor and a dominant-negative mutant of Raf, indicating that p42/44 MAPK was involved. In contrast, neither a p38 MAPK inhibitor nor a JNK inhibitor reduced the stimulatory effect of PGE(2). Involvement of small GTPases was also studied. Dominant-negative Rap inhibited PGE(2) stimulation of the hBNP promoter, but dominant-negative Ras did not. We concluded that PGE(2) stimulates the BNP promoter mainly via EP4, PKA, Rap, and p42/44 MAPK.
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