Sphingosine-1-Phosphate Enhances α1-Adrenergic Vasoconstriction via S1P2–G12/13–ROCK Mediated Signaling

Panta, C. R.; Ruisanchez, Éva; Móré, Dorottya; Dancs, Péter T.; Balogh, Andrea; Fülöp, Ágnes; Kerék, Margit; Proia, Richard L.; Offermanns, Stefan; Tigyi, Gábor; Benyó, Zoltán

doi:10.3390/ijms20246361

Cited by 6 publications

(5 citation statements)

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“…However, a few studies provide evidence that S1P 2 or S1P 3 might play a role in the regulation of heart function. In a recent study, we reported a dominant role of S1P 2 in S1P-induced enhancement of vasoconstrictor stimuli in the circulation [54]. Therefore, in the present study we aimed to characterize the role of these two receptors in mediating CF reduction by S1P.…”

Section: Discussionmentioning

confidence: 89%

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Opposing Roles of S1P3 Receptors in Myocardial Function

Wafa

Koch

Kovács

et al. 2020

Cells

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Sphingosine-1-phosphate (S1P) is a lysophospholipid mediator with diverse biological function mediated by S1P1–5 receptors. Whereas S1P was shown to protect the heart against ischemia/reperfusion (I/R) injury, other studies highlighted its vasoconstrictor effects. We aimed to separate the beneficial and potentially deleterious cardiac effects of S1P during I/R and identify the signaling pathways involved. Wild type (WT), S1P2-KO and S1P3-KO Langendorff-perfused murine hearts were exposed to intravascular S1P, I/R, or both. S1P induced a 45% decrease of coronary flow (CF) in WT-hearts. The presence of S1P-chaperon albumin did not modify this effect. CF reduction diminished in S1P3-KO but not in S1P2-KO hearts, indicating that in our model S1P3 mediates coronary vasoconstriction. In I/R experiments, S1P3 deficiency had no influence on postischemic CF but diminished functional recovery and increased infarct size, indicating a cardioprotective effect of S1P3. Preischemic S1P exposure resulted in a substantial reduction of postischemic CF and cardiac performance and increased the infarcted area. Although S1P3 deficiency increased postischemic CF, this failed to improve cardiac performance. These results indicate a dual role of S1P3 involving a direct protective action on the myocardium and a cardiosuppressive effect due to coronary vasoconstriction. In acute coronary syndrome when S1P may be released abundantly, intravascular and myocardial S1P production might have competing influences on myocardial function via activation of S1P3 receptors.

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Section: Discussionmentioning

confidence: 89%

“…However, this putative mechanism requires further investigation. Moreover, S1P 2 activation might also sensitize the smooth muscle to other vasoconstrictor stimuli, as has been shown in the systemic circulation [54]. S1P is frequently implicated in cardioprotection [21,22,55,56].…”

Section: Discussionmentioning

confidence: 99%

Opposing Roles of S1P3 Receptors in Myocardial Function

Wafa

Koch

Kovács

et al. 2020

Cells

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“…These collective observations suggest that the α2-adrenergic stimulation of adipocytes induces the extracellular release of LPA, resulting, in turn, in the regulation of preadipocyte growth [ 44 ]. Quite interestingly, among these PGs, α-adrenergic, and ROCK signaling mechanisms, it has also been shown that PGF2α-related signaling is closely linked to the Ga12-ROCK signaling pathway [ 45 , 46 ], and α1-adrenergic vasoconstriction is linked with S1P2–G12/13–ROCK-mediated signaling [ 47 ]. However, our previous study indicated that the inhibition of ROCKs by pan-ROCK-is, Rip, or Y27632 additively, but not synergistically, affected the effects that are induced by PGs on DIF+ [ 22 , 48 ], suggesting that both types of signaling may be independent in terms of the DIF+ in 3T3-L1 cells.…”

Section: Discussionmentioning

confidence: 99%

Brimonidine Modulates the ROCK1 Signaling Effects on Adipogenic Differentiation in 2D and 3D 3T3-L1 Cells

et al. 2022

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The additive effects of an α2-adrenergic agonist, brimonidine (BRI), on the pan-ROCK inhibitor (ROCK-i), ripasudil (Rip), and the ROCK2-I, KD025, on adipogenic differentiation (DIF+) were examined using two- or three-dimension (2D or 3D) cultures of 3T3-L1 cells. The following analyses were carried out: (1) lipid staining (2D and 3D), (2) real-time measurements of cellular metabolism (2D), (3) mRNA expression of DIF+ related genes and extracellular matrix molecules (ECMs) including collagen (Col)-1, -4, and -6, and fibronectin (Fn), and (4) the sizes and physical properties of the 3D spheroids. The findings indicate that DIF+ induced (1) a substantial enhancement in lipid staining and enhanced expression of the Pparγ and Fabp4 genes, (2) significantly larger and softer 3D spheroids, and (3) down-regulation of Col1 and Fn and up-regulation of Col4 and Col6 genes. Treatment with Rip alone caused a significant enhancement in adipogenesis of both the 2D and 3D cultured 3T3-L1 cells and in the physical properties of the 3D spheroids; these effects were substantially inhibited by BRI, and the effects induced by BRI or KD025 were not insignificant. These collective findings indicate that the addition of BRI inhibited the Rip-induced enhancement of DIF+ in 3T3-L1 cells, presumably by modulating ROCK1 signaling.

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“…S1P may cause the relaxation of vascular smooth muscle since endothelial cell nitric oxide synthase (eNOS) is activated in the endothelium through the PI3K/Akt process, which occurs downstream of the S1P 1-3 /G i signal pathways. However, since the signal transduction pathway of S1P (S1P 2 and S1P 3 ) is involved in PLC/IP 3 and Rho/Rho-kinase, which are related to Ca 2+ dynamics and Ca 2+ sensitization, respectively, S1P can generate tension in vascular smooth muscle with Ca 2+ signal pathways similar to trachea [12,107]. Previous reports have demonstrated that S1P causes contraction in coronary artery with an increase in intracellular concentration of Ca 2+ (Ca 2+ dynamics) and Rho-kinase activation (Ca 2+ sensitization) [108] (Figure 5), and that S1P also causes contraction in the aorta with an increase in the intracellular Ca 2+ concentration through SOCE [109] (Figure 5).…”

Section: Effects Of Smooth Musclementioning

confidence: 99%

Involvement of Lysophospholipids in Pulmonary Vascular Functions and Diseases

Kume,

Harigane,

Rikimaru

2024

Biomedicines

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Extracellular lysophospholipids (lysophosphatidic acid, lysophosphatidylcholine, sphingosine 1-phosphate, etc.), which are synthesized from phospholipids in the cell membrane, act as lipid mediators, and mediate various cellular responses in constituent cells in the respiratory system, such as contraction, proliferation, migration, and cytoskeletal organization. In addition to these effects, the expression of the adhesion molecules is enhanced by these extracellular lysophospholipids in pulmonary endothelial cells. These effects are exerted via specific G protein-coupled receptors. Rho, Ras, and phospholipase C (PLC) have been proven to be their signaling pathways, related to Ca2+ signaling due to Ca2+ dynamics and Ca2+ sensitization. Therefore, lysophospholipids probably induce pulmonary vascular remodeling through phenotype changes in smooth muscle cells, endothelial cells, and fibroblasts, likely resulting in acute respiratory distress syndrome due to vascular leak, pulmonary hypertension, and pulmonary fibrosis. Moreover, lysophospholipids induce the recruitment of inflammatory cells to the lungs via the enhancement of adhesion molecules in endothelial cells, potentially leading to the development of asthma. These results demonstrate that lysophospholipids may be novel therapeutic targets not only for injury, fibrosis, and hypertension in the lung, but also for asthma. In this review, we discuss the mechanisms of the effects of lysophospholipids on the respiratory system, and the possibility of precision medicine targeting lysophospholipids as treatable traits of these diseases.

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Sphingosine-1-Phosphate Enhances α1-Adrenergic Vasoconstriction via S1P2–G12/13–ROCK Mediated Signaling

Cited by 6 publications

References 70 publications

Opposing Roles of S1P3 Receptors in Myocardial Function

Opposing Roles of S1P3 Receptors in Myocardial Function

Brimonidine Modulates the ROCK1 Signaling Effects on Adipogenic Differentiation in 2D and 3D 3T3-L1 Cells

Involvement of Lysophospholipids in Pulmonary Vascular Functions and Diseases

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