Alterations to Sphingomyelin Metabolism Affect Hemostasis and Thrombosis, 2023, Wang et al.

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Alterations to Sphingomyelin Metabolism Affect Hemostasis and Thrombosis
Jue Wang; Shiva Keshava; Kaushik Das; Richard Kolesnick; Xian-Cheng Jiang; Usha R. Pendurthi; L. Vijaya Mohan Rao

BACKGROUND: Our recent studies suggest that sphingomyelin levels in the plasma membrane influence TF (tissue factor) procoagulant activity. The current study was performed to investigate how alterations to sphingomyelin metabolic pathway would affect TF procoagulant activity and thereby affect hemostatic and thrombotic processes.

METHODS: Macrophages and endothelial cells were transfected with specific siRNAs or infected with adenoviral vectors to alter sphingomyelin levels in the membrane. TF activity was measured in factor X activation assay. Saphenous vein incision–induced bleeding and the inferior vena cava ligation–induced flow restriction mouse models were used to evaluate hemostasis and thrombosis, respectively.

RESULTS: Overexpression of SMS (sphingomyelin synthase) 1 or SMS2 in human monocyte-derived macrophages suppresses ATP-stimulated TF procoagulant activity, whereas silencing SMS1 or SMS2 increases the basal cell surface TF activity to the same level as of ATP-decrypted TF activity. Consistent with the concept that sphingomyelin metabolism influences TF procoagulant activity, silencing of acid sphingomyelinase or neutral sphingomyelinase 2 or 3 attenuates ATP-induced enhanced TF procoagulant activity in macrophages and endothelial cells. Niemann-Pick disease fibroblasts with a higher concentration of sphingomyelin exhibited lower TF activity compared with wild-type fibroblasts. In vivo studies revealed that LPS+ATP-induced TF activity and thrombin generation were attenuated in ASMase −/− mice, while their levels were increased in SMS2 −/− mice. Further studies revealed that acid sphingomyelinase deficiency leads to impaired hemostasis, whereas SMS2 deficiency increases thrombotic risk.

CONCLUSIONS: Overall, our data indicate that alterations in sphingomyelin metabolism would influence TF procoagulant activity and affect hemostatic and thrombotic processes.

HIGHLIGHTS

• Overexpression or inhibition of sphingomyelin by silencing SMS1 (sphingomyelin synthase 1), SMS2, or SMase in different cell types modulated TF (tissue factor) activity on the cell surface and released extracellular vesicles.

• In vivo studies revealed that LPS+ATP-induced TF activity and thrombin generation were attenuated in ASMase −/− mice, while their levels were increased in SMS2 −/− mice.

• Studies using the saphenous vein injury bleeding model and inferior vena cava ligation model showed impaired hemostasis and reduced thrombus formation in ASMase −/− mice, whereas enhanced hemostatic activity and thrombus formation in SMS2 −/− mice.

• Overall, our data indicate that changes in the SM metabolism influence hemostasis and thrombosis in vitro and in vivo through modulation TF encryption and decryption processes.

Link | PDF (Arteriosclerosis, Thrombosis, and Vascular Biology)

 

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Sphingomyelin metabolism is altered in many disease settings, including atherosclerosis, diabetes, sepsis, and cancer, the same disease settings were also known to induce aberrant expression or activation of TF [tissue factor]. Several pathogenic stimuli, for example, LPS, cytokines, ATP, irradiation, and bacterial and viral infections that promote TF procoagulant activity, were also found to translocate lysosomal ASMase [acid sphingomyelinase] to the outer leaflet or secrete intracellular ASMase to the extracellular space.

Finally, although our present data are consistent with the hypothesis sphingomyelin metabolism influences TF procoagulant activity, and thus affects hemostatic and thrombotic processes, current experimental approaches make it difficult to conclude firmly that changes in TF procoagulant activity associated with sphingomyelin levels in the plasma membrane is solely responsible for the observed defects seen in [...] ASMase −/− and SMS2 −/− mice.

Global alterations in sphingomyelin metabolism may, in addition to affecting TF activity in monocytes and other cell types, also affect platelet function, the function of other membrane-dependent procoagulant complexes, and the formation of neutrophil extracellular traps. All the above processes could affect hemostatic and thrombotic processes in vivo.

 

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Sphingomyelins may also be affected by diet, and pwDiseases may have different diets than their controls.