Dihydrosphingosine driven enrichment of sphingolipids attenuates TGFß induced collagen synthesis in cardiac fibroblasts.
Int J Cardiol Heart Vasc
; 35: 100837, 2021 Aug.
Article
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| MEDLINE
| ID: mdl-34277924
The sphingolipid de novo synthesis pathway, encompassing the sphingolipids, the enzymes and the cell membrane receptors, are being investigated for their role in diseases and as potential therapeutic targets. The intermediate sphingolipids such as dihydrosphingosine (dhSph) and sphingosine (Sph) have not been investigated due to them being thought of as precursors to other more active lipids such as ceramide (Cer) and sphingosine 1 phosphate (S1P). Here we investigated their effects in terms of collagen synthesis in primary rat neonatal cardiac fibroblasts (NCFs). Our results in NCFs showed that both dhSph and Sph did not induce collagen synthesis, whilst dhSph reduced collagen synthesis induced by transforming growth factor ß (TGFß). The mechanisms of these inhibitory effects were associated with the increased activation of the de novo synthesis pathway that led to increased dihydrosphingosine 1 phosphate (dhS1P). Subsequently, through a negative feedback mechanism that may involve substrate-enzyme receptor interactions, S1P receptor 1 expression (S1PR1) was reduced.
Akt, protein kinase B; CTGF, connective tissue growth factor; Cardiac fibroblasts; Cer, ceramide; Cer1P, ceramide 1 phosphate; Coll1a1, collagen 1a1; Collagen synthesis; Degs1, dihydroceramide desaturase 1 gene; Des-1, dihydroceramide desaturase 1 enzyme; Dihydrosphingosine; ECM, extracellular matrix inhibitor of nuclear kappa B (NFKß) kinase alpha and beta (IKKα/ß); MA3PK, mitogen activated protein kinase kinase kinase; MAPK, mitogren activated protein kinase; MI, myocardial infarct; MMP2, matrix metalloproteinase 2; NCF, neonatal cardiac fibroblasts; RPS6, ribosomal protein S6; S1P, sphingosine-1 Phosphate; S1PR1, sphingosine -1-phosphate receptor 1; S1PRs, sphingosine 1 phosphate receptor 1-5; SK1, sphingosine kinase 1; Sph, sphingosine; Sphingolipid; TAK1, transforming growth factor ß activating kinase 1; TGFß; TGFß, transforming growth factor ß; TIMP1, tissue inhibitor of metalloproteinase 1; d7dhSph, deuterated dihydrosphingosine; dhCer, dihydroceramide; dhS1P, dihydrosphingosine 1 phosphate; mTOR, mammalian target for rapamycin
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Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
Int J Cardiol Heart Vasc
Año:
2021
Tipo del documento:
Article
País de afiliación:
Australia
Pais de publicación:
Irlanda