Ceramide kinase mediates toll‐like receptor 4‐induced inflammation in vascular smooth muscle cells

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Sphingolipid metabolites have recently been implicated in toll‐like receptor 4 (TLR4) signaling. Activation of lipopolysaccharide (LPS)‐induced TLR4 signaling is dependent upon production of ceramide by acid sphingomyelinase (Cuschieri et al, Surg Infect, 2007). Yet, the role of ceramide metabolites to contribute to TLR4‐induced inflammatory responses has not been investigated. Specifically, we now hypothesize that TLR4‐induced proliferation and inflammation in vascular smooth muscle cells (VSMC) is dependent upon activated ceramide kinase (CERK) and resulting production of ceramide‐1‐phosphate (C1P). We demonstrate that LPS treatment of A7r5 VSMC leads to elevated CERK mRNA and protein expression. This increased expression of CERK correlates with increased LPS‐induced C1P mass, quantified by LC/MS/MS analysis. We show that LPS‐ and ceramide‐1‐phosphate‐, but not ceramide‐treatment, leads to hallmarks of vascular inflammatory disease, including increased VSMC proliferation, positive remodeling, and production of inflammatory mediators. In addition, LPS‐treated mouse blood samples had increased levels of ceramide‐1‐phosphate at the expense of ceramide. Taken together, our studies implicate ceramide‐1‐phosphate as a potential biomarker and /or mediator of vascular inflammation in diseases such as atherosclerosis or restenosis after angioplasty. These studies were funded, in part, by NIH RO1 HL076789 to MK.