In:
Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 111, No. 12 ( 2005-03-29), p. 1510-1516
Abstract:
Background— Diacylglycerol (DAG) is a lipid second messenger that transiently accumulates in cells stimulated by endothelin-1 (ET-1) and other Gαq protein-coupled receptor agonists. Diacylglycerol kinase (DGK) is thought to be an enzyme that controls the cellular levels of DAG by converting it to phosphatidic acid; however, the functional role of DGK has not been examined in cardiomyocytes. Because DGK inactivates DAG, a strong activator of protein kinase C (PKC), we hypothesized that DGK inhibited ET-1–induced activation of a DAG-PKC signaling cascade and subsequent cardiomyocyte hypertrophy. Methods and Results— Real-time reverse transcription-polymerase chain reaction demonstrated a significant increase of DGK-ζ mRNA by ET-1 in cardiomyocytes. To determine the functional role of DGK-ζ, we overexpressed DGK-ζ in cardiomyocytes using a recombinant adenovirus encoding rat DGK-ζ (Ad-DGKζ). ET-1–induced translocation of PKC-ε was blocked by Ad-DGKζ ( P 〈 0.01). Ad-DGKζ also inhibited ET-1–induced activation of extracellular signal-regulated kinase ( P 〈 0.01). Luciferase reporter assay revealed that ET-1–mediated increase of activator protein-1 (AP1) DNA-binding activity was significantly inhibited by DGK-ζ ( P 〈 0.01). In cardiomyocytes transfected with DGK-ζ, ET-1 failed to cause gene induction of atrial natriuretic factor, increases in [ 3 H]-leucine uptake, and increases in cardiomyocyte surface area. Conclusions— We demonstrated for the first time that DGK-ζ blocked ET-1–induced activation of the PKC-ε–ERK-AP1 signaling pathway, atrial natriuretic factor gene induction, and resultant cardiomyocyte hypertrophy. DGK-ζ might act as a negative regulator of hypertrophic program in response to ET-1, possibly by controlling cellular DAG levels.
Type of Medium:
Online Resource
ISSN:
0009-7322
,
1524-4539
DOI:
10.1161/01.CIR.0000159339.00703.22
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2005
detail.hit.zdb_id:
1466401-X
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