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Dihydrosphingosine driven enrichment of sphingolipids attenuates TGFβ induced collagen synthesis in cardiac fibroblasts.

ABSTRACT: 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 β (TGFβ). 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.

SUBMITTER: Magaye RR

PROVIDER: S-EPMC8264607 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Cardiac fibroblasts play important functional and pathophysiological roles. Intracellular ("intracrine") angiotensin-II (Ang-II) signaling regulates intercellular communication, excitability, and gene expression in cardiomyocytes; however, the existence and role of intracrine Ang-II signaling in cardiac fibroblasts is unstudied. Here, we evaluated the localization of Ang-II receptors on atrial fibroblast nuclei and associated intracrine effects of potential functional significance. Immunoblots of subcellular protein-fractions from isolated canine atrial fibroblasts indicated the presence of nuclear Ang-II type 1 receptors (AT1Rs) and Ang-II type 2 receptors (AT2Rs). Fluorescein isothiocyanate-Ang-II binding displaceable by AT1R- and AT2R-blockers was present on isolated fibroblast nuclei. G-protein subunits, including Gαq/11, Gαi/3, and Gβ, were observed in purified fibroblast nuclear fractions by immunoblotting and intact-fibroblast nuclei by confocal immunocytofluorescence microscopy. Nuclear AT1Rs and AT2Rs regulated de novo RNA synthesis ([α32P]UTP incorporation) via IP3R- and NO-dependent pathways, respectively. In intact cultured fibroblasts, intracellular Ang-II release by photolysis of a membrane-permeable caged Ang-II analog led to IP3R-dependent nucleoplasmic Ca2+-liberation, with IP3R3 being the predominant nuclear isoform. Intracellular Ang-II regulated fibroblast proliferation ([3H]thymidine incorporation), collagen-1A1 mRNA-expression, and collagen secretion. Intracellular Ang-II and nuclear AT1R protein levels were significantly increased in a heart failure model in which atrial fibrosis underlies atrial fibrillation. Fibroblast nuclei possess AT1R and AT2R binding sites that are coupled to intranuclear Ca2+-mobilization and NO liberation, respectively. Intracellular Ang-II signaling regulates fibroblast proliferation, collagen gene expression, and collagen secretion. Heart failure upregulates Ang-II intracrine signaling-components in atrial fibroblasts. These results show for the first time that nuclear angiotensin-II receptor activation and intracrine Ang-II signaling control fibroblast function and may have pathophysiological significance.

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Dihydrosphingosine driven enrichment of sphingolipids attenuates TGFβ induced collagen synthesis in cardiac fibroblasts.

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