Sphingosine-1-Phosphate Protects Against the Development of Cardiac Remodeling via Sphingosine Kinase 2 and the S1PR2/ERK Pathway

Yan, Hui; Zhao, Hu; Yi, Shaowei; Zhuang, Hang; Wang, Daowen; Jiang, Jian-Gang; Shen, Guifen

doi:10.1007/s11596-022-2600-x

Cited by 5 publications

(3 citation statements)

References 31 publications

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“…40,41 In addition, SPHK2a isoform is species-specific, expressed in humans but not in mice, 39 suggesting possible differences between human and rodent model findings. Previously, a protective role by SPHK2 against cardiac fibrosis 42 was reported. However, no changes in the cardiac function of SPHK2 knockout mice (Figure S2B) were identified.…”

Section: Discussionmentioning

confidence: 97%

Altered Smooth Muscle Cell Histone Acetylome by the SPHK2/S1P Axis Promotes Pulmonary Hypertension

Ranasinghe,

Holohan,

Borger

et al. 2023

Circulation Research

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BACKGROUND: Epigenetic regulation of vascular remodeling in pulmonary hypertension (PH) is poorly understood. Transcription regulating, histone acetylation code alters chromatin accessibility to promote transcriptional activation. Our goal was to identify upstream mechanisms that disrupt epigenetic equilibrium in PH. METHODS: Human pulmonary artery smooth muscle cells (PASMCs), human idiopathic pulmonary arterial hypertension (iPAH):human PASMCs, iPAH lung tissue, failed donor lung tissue, human pulmonary microvascular endothelial cells, iPAH:PASMC and non-iPAH:PASMC RNA-seq databases, NanoString nCounter, and cleavage under targets and release using nuclease were utilized to investigate histone acetylation, hyperacetylation targets, protein and gene expression, sphingolipid activation, cell proliferation, and gene target identification. SPHK2 (sphingosine kinase 2) knockout was compared with control C57BL/6NJ mice after 3 weeks of hypoxia and assessed for indices of PH. RESULTS: We identified that Human PASMCs are vulnerable to the transcription-promoting epigenetic mediator histone acetylation resulting in alterations in transcription machinery and confirmed its pathological existence in PH:PASMC cells. We report that SPHK2 is elevated as much as 20-fold in iPAH lung tissue and is elevated in iPAH:PASMC cells. During PH pathogenesis, nuclear SPHK2 activates nuclear bioactive lipid S1P (sphingosine 1-phosphate) catalyzing enzyme and mediates transcription regulating histone H3K9 acetylation (acetyl histone H3 lysine 9 [Ac-H3K9]) through EMAP (endothelial monocyte activating polypeptide) II. In iPAH lungs, we identified a 4-fold elevation of the reversible epigenetic transcription modulator Ac-H3K9:H3 ratio. Loss of SPHK2 inhibited hypoxic-induced PH and Ac-H3K9 in mice. We discovered that pulmonary vascular endothelial cells are a priming factor of the EMAP II/SPHK2/S1P axis that alters the acetylome with a specificity for PASMC, through hyperacetylation of histone H3K9. Using cleavage under targets and release using nuclease, we further show that EMAP II–mediated SPHK2 has the potential to modify the local transcription machinery of pluripotency factor KLF4 (Krüppel-like factor 4) by hyperacetylating KLF4 Cis-regulatory elements while deletion and targeted inhibition of SPHK2 rescues transcription altering Ac-H3K9. CONCLUSIONS: SPHK2 expression and its activation of the reversible histone H3K9 acetylation in human pulmonary artery smooth muscle cell represent new therapeutic targets that could mitigate PH vascular remodeling.

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Section: Discussionmentioning

confidence: 97%

Altered Smooth Muscle Cell Histone Acetylome by the SPHK2/S1P Axis Promotes Pulmonary Hypertension

Ranasinghe,

Holohan,

Borger

et al. 2023

Circulation Research

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“…RSV's capacity to inhibit SPH kinase activity might reduce cardio protection, provided by S1P associated with the HDL, and S1P-dependent activation of pro-survival signaling through pathways such as the PI3K/Akt and MAPK pathways [101][102][103][104][105]. However, S1P also induces cardiac hypertrophy, decreases the heart rate, reduces ventricular contraction and exerts artery vasoconstriction, adverse effects that can theoretically be improved by inhibiting SPH kinase activity or expression with resveratrol [106][107][108][109].…”

Section: Effects Of Resveratrol On Sphingolipid Metabolism: Possible ...mentioning

confidence: 99%

Sphingolipid Levels and Signaling via Resveratrol and Antioxidant Actions in Cardiometabolic Risk and Disease

2023

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Resveratrol (RSV) is a phenolic compound with strong antioxidant activity, which is generally associated with the beneficial effects of wine on human health. All resveratrol-mediated benefits exerted on different systems and pathophysiological conditions are possible through resveratrol’s interactions with different biological targets, along with its involvement in several key cellular pathways affecting cardiometabolic (CM) health. With regard to its role in oxidative stress, RSV exerts its antioxidant activity not only as a free radical scavenger but also by increasing the activity of antioxidant enzymes and regulating redox genes, nitric oxide bioavailability and mitochondrial function. Moreover, several studies have demonstrated that some RSV effects are mediated by changes in sphingolipids, a class of biolipids involved in a number of cellular functions (e.g., apoptosis, cell proliferation, oxidative stress and inflammation) that have attracted interest as emerging critical determinants of CM risk and disease. Accordingly, this review aimed to discuss the available data regarding the effects of RSV on sphingolipid metabolism and signaling in CM risk and disease, focusing on oxidative stress/inflammatory-related aspects, and the clinical implications of this relationship.

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“…HO-1 effectively scavenges ROS, including peroxides, peroxynitrite, hydroxyl radicals, and superoxide radicals [18]. HO-1 expression is activated by LPS, which helps inhibit inflammation and oxidative damage by reducing NO production and protecting macrophages against oxidative stress [19]. Therefore, the mRNA levels of these cytokine genes may work as valid indicators to evaluate antioxidant and anti-inflammatory effects.…”

Section: Introductionmentioning

confidence: 99%

Antioxidant Polyphenols from Lespedeza bicolor Turcz. Honey: Anti-Inflammatory Effects on Lipopolysaccharide-Treated RAW 264.7 Macrophages

Ren,

Li,

Luo

et al. 2023

Antioxidants

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Although the honey produced by Lespedeza bicolor Turcz. is precious because of its medicinal value, its pharmacological mechanism is still unclear. Here, its anti-inflammatory and antioxidant functions on lipopolysaccharide (LPS)-treated murine RAW 264.7 macrophages were analyzed using targeted and non-targeted metabolomics. Results showed that twelve polyphenols were identified in L. bicolor honey using UHPLC-QQQ-MS/MS. L. bicolor honey extract could scavenge the free radicals DPPH• and ABTS+ and reduce Fe3+. Furthermore, pretreatment with L. bicolor honey extract significantly decreased NO production; suppressed the expression of COX-2, IL-10, TNF-α, and iNOS; and upregulated HO-1′s expression in the cells with LPS application. UHPLC-Q-TOF-MS/MS-based metabolomics results revealed that L. bicolor honey extract could protect against inflammatory damage caused by LPS through the reduced activation of sphingolipid metabolism and necroptosis pathways. These findings demonstrate that L. bicolor honey possesses excellent antioxidant and anti-inflammatory activities.

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Sphingosine-1-Phosphate Protects Against the Development of Cardiac Remodeling via Sphingosine Kinase 2 and the S1PR2/ERK Pathway

Cited by 5 publications

References 31 publications

Altered Smooth Muscle Cell Histone Acetylome by the SPHK2/S1P Axis Promotes Pulmonary Hypertension

Altered Smooth Muscle Cell Histone Acetylome by the SPHK2/S1P Axis Promotes Pulmonary Hypertension

Sphingolipid Levels and Signaling via Resveratrol and Antioxidant Actions in Cardiometabolic Risk and Disease

Antioxidant Polyphenols from Lespedeza bicolor Turcz. Honey: Anti-Inflammatory Effects on Lipopolysaccharide-Treated RAW 264.7 Macrophages

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