Endothelin-1 Stimulates Small Artery VCAM-1 Expression through p38MAPK-Dependent Neutral Sphingomyelinase

Ohanian, Jacqueline; Forman, Simon; Katzenberg, Gideon; Ohanian, Vasken

doi:10.1159/000336649

Cited by 21 publications

(14 citation statements)

References 105 publications

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“…In this regard, it has been reported that ET-1 stimulates nSMase activity through a p38MAPK-dependent pathway, leading to vascular cell adhesion molecule (VCAM-1) expression (38). The activation of the BK-B 1 receptor leads to the activation of SMase, and the generated ceramide induces vasodilatation in rat mesenteric small arteries (25).…”

Section: Discussionmentioning

confidence: 99%

Involvement of neutral sphingomyelinase in the angiotensin II signaling pathway

Bautista-Pérez

Valle-Mondragón

Cano-Martı́nez

et al. 2015

American Journal of Physiology-Renal Physiology

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The possibility that angiotensin II (ANG II) exerts its effects through the activation of neutral sphingomyelinase (nSMase) has not been tested in kidneys. The results of the present study provide evidence for the activity and expression of nSMase in rat kidneys. In isolated perfused rat kidney, ANG II-induced renal vasoconstriction was inhibited by GW4869, an inhibitor of nSMase. We used nSMase for investigating the signal transduction downstream of ceramide. nSMase constricted the renal vasculature. An inhibitor of ceramidase (CDase), N-oleoylethanolamine (OEA), enhanced either ANG II-or nSMase-induced renal vasoconstriction. To demonstrate the interaction between the nSMase and cytosolic phospholipase A 2 (cPLA2) signal transduction pathways, we evaluated the response to nSMase in the presence and absence of inhibitors of arachidonic acid (AA) metabolism: arachidonyl trifluoromethyl ketone (AACOCF3), an inhibitor of cPLA2; 5,8,11,14-eicosatetraynoic acid (ETYA), an inhibitor of all AA pathways; indomethacin, an inhibitor of cyclooxygenase (COX); furegrelate, a thromboxane A 2 (TxA2)-synthase inhibitor; and SQ29548, a TxA 2-receptor antagonist. In these experiments, the nSMase-induced renal vasoconstriction decreased. ANG II or nSMase was associated with an increase in the release of thromboxane B2 (TxB2) in the renal perfusate of isolated perfused rat kidney. In addition, the coexpression of the ceramide with cPLA2, was found in the smooth muscle layer of intrarenal vessels. Our results suggest that ANG II stimulates ceramide formation via the activation of nSMase; thus ceramide may indirectly regulate vasoactive processes that modulate the activity of cPLA2 and the release of TxA2. renal vasoconstriction; angiotensin II; sphingomyelinase; phospholipase A2; cyclooxygenase; thromboxane A2 SPHINGOLIPIDS ARE A FAMILY of lipids that play essential roles as structural cell membrane components and also serve as substrates for enzymes that generate second messengers involved in cell signaling. Thus sphingolipids can be hydrolyzed by sphingomyelinases (SMases) (43). SMases are divided into three major classes, alkaline, acid, and neutral, according to the optimal pH for their activity, primary structure, and localization (15). Acid and alkaline SMases contribute to the hydrolysis of sphingomyelin in the luminal border of cells, in the extracellular space, or in the endosomal system, whereas neutral SMase (nSMase) functions in the inner leaflet of the plasma membrane (32). SMases cleave the phosphodiester linkage of sphingomyelin to produce phosphocholine and ceramide.

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Section: Discussionmentioning

confidence: 99%

Involvement of neutral sphingomyelinase in the angiotensin II signaling pathway

Bautista-Pérez

Valle-Mondragón

Cano-Martı́nez

et al. 2015

American Journal of Physiology-Renal Physiology

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“…In that context, the effect of the physiologic vasoconstrictors endothelin-1 (ET-1) on nSMase2 was studied. ET-1 activates nSMase2 to induce VCAM-1 expression in rat small mesenteric artery (Ohanian et al , 2012). Probing the system further, the effect of dietary Mg 2+ deficiency was studied.…”

Section: Nsmase2 As a Regulator Of Biological Functionsmentioning

confidence: 99%

Roles and regulation of neutral sphingomyelinase-2 in cellular and pathological processes

Shamseddine

Airola²,

Hannun³

2015

Advances in Biological Regulation

185

161

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Our understanding of the functions of ceramide signaling has advanced tremendously over the past decade. In this review, we focus on the roles and regulation of neutral sphingomyelinase 2 (nSMase2), an enzyme that generates the bioactive lipid ceramide through the hydrolysis of the membrane lipid sphingomyelin. A large body of work has now implicated nSMase2 in a diverse set of cellular functions, physiological processes, and disease pathologies. We discuss different aspects of this enzyme’s regulation from transcriptional, post-translational, and biochemical. Furthermore, we highlight nSMase2 involvement in cellular processes including inflammatory signaling, exosome generation, cell growth, and apoptosis, which in turn play important roles in pathologies such as cancer metastasis, Alzheimer’s disease, and other organ systems disorders. Lastly, we examine avenues where targeted nSMase2-inhibition may be clinically beneficial in disease scenarios.

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“…Among the mechanisms possibly involved in the activation of nSMase2 by MMP2, we investigated the role of p38MAPK, which is early activated in response to agents such as TNF-α [18] or endothelin-1 [24] . Results presented in Fig.…”

Section: Resultsmentioning

confidence: 99%

Annexin II-dependent actin remodelling evoked by hydrogen peroxide requires the metalloproteinase/sphingolipid pathway

et al. 2015

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Actin remodeling is a dynamic process associated with cell shape modification occurring during cell cycle and proliferation. Oxidative stress plays a role in actin reorganization via various systems including p38MAPK. Beside, the mitogenic response evoked by hydrogen peroxide (H2O2) in fibroblasts and smooth muscle cells (SMC) involves the metalloproteinase (MMPs)/sphingomyelinase 2 (nSMase2) signaling pathway. The aim of this work was to investigate whether this system plays a role in actin remodeling induced by H2O2.Low H2O2 dose (5 µM) rapidly triggered a signaling cascade leading to nSMase2 activation, src and annexin 2 (AnxA2) phosphorylation, and actin remodeling, in fibroblasts and SMC. These events were blocked by pharmacological inhibitors of MMPs (Ro28-2653) and p38MAPK (SB203580), and were lacking in MMP2−/− and in nSMase2-mutant (fro) fibroblasts. Likewise, H2O2 was unable to induce actin remodeling in fro and MMP2−/− fibroblasts or in cells pretreated with p38MAPK, or MMP inhibitors. Finally we show that nSMase2 activation by H2O2, depends on MMP2 and p38MAPK, and is required for the src-dependent phosphorylation of AnxA2, and actin remodeling.Taken together, these findings indicate for the first time that AnxA2 phosphorylation and actin remodeling evoked by oxidative stress depend on the sphingolipid pathway, via MMP2 and p38MAPK.

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Endothelin-1 Stimulates Small Artery VCAM-1 Expression through p38MAPK-Dependent Neutral Sphingomyelinase

Cited by 21 publications

References 105 publications

Involvement of neutral sphingomyelinase in the angiotensin II signaling pathway

Involvement of neutral sphingomyelinase in the angiotensin II signaling pathway

Roles and regulation of neutral sphingomyelinase-2 in cellular and pathological processes

Annexin II-dependent actin remodelling evoked by hydrogen peroxide requires the metalloproteinase/sphingolipid pathway

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