Ceramide activation of RhoA/Rho kinase impairs actin polymerization during aggregated LDL catabolism[S]

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Ceramide activation of RhoA/Rho kinase impairs actin polymerization during aggregated LDL catabolism[S]

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Title: Ceramide activation of RhoA/Rho kinase impairs actin polymerization during aggregated LDL catabolism[S]
Author: Singh, Rajesh K.; Haka, Abigail S.; Brumfield, Alexandria; Grosheva, Inna; Bhardwaj, Priya; Chin, Harvey F.; Xiong, Yuquan; Hla, Timothy; Maxfield, Frederick R.

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Citation: Singh, Rajesh K., Abigail S. Haka, Alexandria Brumfield, Inna Grosheva, Priya Bhardwaj, Harvey F. Chin, Yuquan Xiong, Timothy Hla, and Frederick R. Maxfield. 2017. “Ceramide activation of RhoA/Rho kinase impairs actin polymerization during aggregated LDL catabolism[S].” Journal of Lipid Research 58 (10): 1977-1987. doi:10.1194/jlr.M076398. http://dx.doi.org/10.1194/jlr.M076398.
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Abstract: Macrophages use an extracellular, hydrolytic compartment formed by local actin polymerization to digest aggregated LDL (agLDL). Catabolism of agLDL promotes foam cell formation and creates an environment rich in LDL catabolites, including cholesterol and ceramide. Increased ceramide levels are present in lesional LDL, but the effect of ceramide on macrophage proatherogenic processes remains unknown. Here, we show that macrophages accumulate ceramide in atherosclerotic lesions. Using macrophages from sphingosine kinase 2 KO (SK2KO) mice to mimic ceramide-rich conditions of atherosclerotic lesions, we show that SK2KO macrophages display impaired actin polymerization and foam cell formation in response to contact with agLDL. C16-ceramide treatment impaired wild-type but not SK2KO macrophage actin polymerization, confirming that this effect is due to increased ceramide levels. We demonstrate that knockdown of RhoA or inhibition of Rho kinase restores agLDL-induced actin polymerization in SK2KO macrophages. Activation of RhoA in macrophages was sufficient to impair actin polymerization and foam cell formation in response to agLDL. Finally, we establish that during catabolism, macrophages take up ceramide from agLDL, and inhibition of ceramide generation modulates actin polymerization. These findings highlight a critical regulatory pathway by which ceramide impairs actin polymerization through increased RhoA/Rho kinase signaling and regulates foam cell formation.
Published Version: doi:10.1194/jlr.M076398
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5625121/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:34492363
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