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

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. 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. A critical initiating event in atherogenesis is the progressive deposition of LDL in the arterial wall (1.Tabas I. Williams K.J. Boren J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications.Circulation. 2007; 116: 1832-1844Crossref PubMed Scopus (977) Google Scholar). This LDL becomes modified, aggregated, and retained. Macrophages encountering such deposits are unable to use standard phagocytic or endocytic mechanisms to catabolize this aggregated LDL (agLDL). Instead, they form an intimate contact with the agLDL, a lysosomal synapse (LS) (2.Haka A.S. Grosheva I. Chiang E. Buxbaum A.R. Baird B.A. Pierini L.M. Maxfield F.R. Macrophages create an acidic extracellular hydrolytic compartment to digest aggregated lipoproteins.Mol. Biol. Cell. 2009; 20: 4932-4940Crossref PubMed Scopus (88) Google Scholar, 4.Singh R.K. Barbosa-Lorenzi V.C. Lund F.W. Grosheva I. Maxfield F.R. Haka A.S. Degradation of aggregated LDL occurs in complex extracellular sub-compartments of the lysosomal synapse.J. Cell Sci. 2016; 129: 1072-1082Crossref PubMed Scopus (25) Google Scholar). The LS is characterized by local actin polymerization (3.Grosheva I. Haka A.S. Qin C. Pierini L.M. Maxfield F.R. Aggregated LDL in contact with macrophages induces local increases in free cholesterol levels that regulate local actin polymerization.Arterioscler. Thromb. Vasc. Biol. 2009; 29: 1615-1621Crossref PubMed Scopus (33) Google Scholar), exocytosis of lysosomal contents (2.Haka A.S. Grosheva I. Chiang E. Buxbaum A.R. Baird B.A. Pierini L.M. Maxfield F.R. Macrophages create an acidic extracellular hydrolytic compartment to digest aggregated lipoproteins.Mol. Biol. Cell. 2009; 20: 4932-4940Crossref PubMed Scopus (88) Google Scholar), and regions of low pH at macrophage contact sites with agLDL (2.Haka A.S. Grosheva I. Chiang E. Buxbaum A.R. Baird B.A. Pierini L.M. Maxfield F.R. Macrophages create an acidic extracellular hydrolytic compartment to digest aggregated lipoproteins.Mol. Biol. Cell. 2009; 20: 4932-4940Crossref PubMed Scopus (88) Google Scholar). We have shown previously that actin polymerization is important for formation of the LS, because it drives macrophage plasma membrane contact with agLDL (4.Singh R.K. Barbosa-Lorenzi V.C. Lund F.W. Grosheva I. Maxfield F.R. Haka A.S. Degradation of aggregated LDL occurs in complex extracellular sub-compartments of the lysosomal synapse.J. Cell Sci. 2016; 129: 1072-1082Crossref PubMed Scopus (25) Google Scholar). Exocytosis of lysosomal contents into the LS allows delivery of hydrolytic enzymes, such as lysosomal acid lipase and acid SMase residing in the lysosomes, which promote catabolism of agLDL and generation of catabolites such as free cholesterol (3.Grosheva I. Haka A.S. Qin C. Pierini L.M. Maxfield F.R. Aggregated LDL in contact with macrophages induces local increases in free cholesterol levels that regulate local actin polymerization.Arterioscler. Thromb. Vasc. Biol. 2009; 29: 1615-1621Crossref PubMed Scopus (33) Google Scholar, 4.Singh R.K. Barbosa-Lorenzi V.C. Lund F.W. Grosheva I. Maxfield F.R. Haka A.S. Degradation of aggregated LDL occurs in complex extracellular sub-compartments of the lysosomal synapse.J. Cell Sci. 2016; 129: 1072-1082Crossref PubMed Scopus (25) Google Scholar). This free cholesterol promotes macrophage actin polymerization, likely through activation of Rac/Cdc42 GTPases (3.Grosheva I. Haka A.S. Qin C. Pierini L.M. Maxfield F.R. Aggregated LDL in contact with macrophages induces local increases in free cholesterol levels that regulate local actin polymerization.Arterioscler. Thromb. Vasc. Biol. 2009; 29: 1615-1621Crossref PubMed Scopus (33) Google Scholar). Free cholesterol at the LS that is subsequently internalized by the macrophage promotes foam cell formation (3.Grosheva I. Haka A.S. Qin C. Pierini L.M. Maxfield F.R. Aggregated LDL in contact with macrophages induces local increases in free cholesterol levels that regulate local actin polymerization.Arterioscler. Thromb. Vasc. Biol. 2009; 29: 1615-1621Crossref PubMed Scopus (33) Google Scholar). We have postulated that release of free cholesterol from macrophages into the extracellular space during agLDL catabolism may be a precursor for the formation of extracellular cholesterol crystals. Apart from free cholesterol, other metabolites are also produced in the microenvironment of the plaque. In the atherosclerotic plaque, lesional agLDL is known to be rich in ceramide, and it contains 10- to 50-fold-higher content of ceramide when compared with plasma LDL (5.Schissel S.L. Tweedie-Hardman J. Rapp J.H. Graham G. Williams K.J. Tabas I. Rabbit aorta and human atherosclerotic lesions hydrolyze the sphingomyelin of retained low-density lipoprotein. Proposed role for arterial-wall sphingomyelinase in subendothelial retention and aggregation of atherogenic lipoproteins.J. Clin. Invest. 1996; 98: 1455-1464Crossref PubMed Scopus (269) Google Scholar). Ceramides are usually found within cellular membranes, and studies have shown that they can act as potent signaling mediators regulating processes such as cell differentiation and proliferation (6.Sharma K. Shi Y. The yins and yangs of ceramide.Cell Res. 1999; 9: 1-10Crossref PubMed Scopus (19) Google Scholar). Ceramide can be generated by acid SMase that exists in two forms, a lysosomal acid SMase (L-SMase) that requires a low pH for activity (7.Callahan J.W. Jones C.S. Davidson D.J. Shankaran P. The active site of lysosomal sphingomyelinase: evidence for the involvement of hydrophobic and ionic groups.J. Neurosci. Res. 1983; 10: 151-163Crossref PubMed Scopus (36) Google Scholar) and a secretory acid SMase (S-SMase), which is not localized to the lysosome and can function at neutral pH (8.Schissel S.L. Jiang X. Tweedie-Hardman J. Jeong J. Rapp J.H. Williams K.J. Tabas I. a of the acid sphingomyelinase can hydrolyze atherogenic at neutral for atherosclerotic Biol. PubMed Scopus Google Scholar). to be for of sphingomyelin to ceramide in LDL, in cellular signaling and and of secretory and lysosomal acid 2009; PubMed Scopus Google Scholar). The pathway of generation of ceramide is through activation of which can sphingomyelin to ceramide J. P. C. a pathway for PubMed Scopus Google Scholar). of ceramide through activation of occurs in response to and and can be of as a cell conditions of ceramide and PubMed Scopus Google Scholar, K. Ceramide an for PubMed Scopus Google Scholar). function of acid SMase in in A and in human and in from with Res. PubMed Google Scholar), and of acid SMase in mice in the to P. C. human and mice are in 1996; PubMed Scopus Google Scholar). to the role of ceramide in in the it as a critical in atherosclerotic processes J. P. C. a pathway for PubMed Scopus Google Scholar). studies have on the role of ceramide in of atherogenic This is because SMase shown to and aggregation of LDL S.L. Tabas I. A.R. Jiang X. Increased sphingomyelin content of plasma in mice and and with Clin. Invest. PubMed Scopus Google Scholar). when ceramide is in a of ceramide is because it is are In this we C16-ceramide as and macrophages from sphingosine kinase 2 KO (SK2KO) found previously to levels of Y. Haka A.S. Maxfield F.R. E. are not for in Biol. J. Biol. PubMed Scopus Google Scholar). We to levels of ceramide that macrophages in the microenvironment of the and to the role of ceramide in agLDL catabolism and foam cell formation. We that macrophages accumulate ceramide in atherosclerotic a we show that this ceramide can actin polymerization at the LS and foam cell formation in response to agLDL in a RhoA/Rho We also show that ceramide from agLDL can be up by macrophages and can regulate macrophage agLDL These highlight a regulatory pathway that macrophages use to agLDL catabolism and a in which to ceramide signaling during foam cell formation and macrophages and macrophages in with and in a at and at low to be macrophages as was from mice of We and from wild-type kinase and mice on a previously Y. Haka A.S. Maxfield F.R. E. are not for in Biol. J. Biol. PubMed Scopus Google Scholar, J. role of sphingosine 2 in macrophage during PubMed Scopus Google Scholar, E. C. S.L. and PubMed Scopus Google and from and wild-type previously K. K. K. sphingomyelinase a of A and 10: PubMed Scopus Google and for by in with and with in a at and KO mice in the in a environment at and in with by the and and from C16-ceramide and from and from was from Rho was from 2 was from Cell and from was a from and a from and mice from and on a for and with and for in at in a of in and at in of in in and in the and into a and for with for macrophages a for at at and at for 2 at Ceramide was a at at and at for 2 at was in with a a LDL was from plasma as previously J.H. The and of in human Clin. Invest. PubMed Scopus Google Scholar). was from LDL was of LDL was aggregated by for X. G. Maxfield F.R. Tabas I. cellular during the of macrophages with or aggregated low lipoprotein Biol. 1999; PubMed Scopus Google Scholar). was by with in at with for to The was with to with on with a or a or actin with a of with Cell was by was by the cell and by cell ceramide with in for at with and subsequently for at by in with at in to for at was in by in with to foam cell for with with in for at with and or in for at by in to or to treatment with for with in for at and for actin of or in in for with and from to macrophages and to and at for was to and to macrophages on for to agLDL and SK2KO with the Cell in or a of RhoA to a of 2 to and to and into and for Cell and into for or for of knockdown RhoA levels by RhoA in with polymerization was as previously (3.Grosheva I. Haka A.S. Qin C. Pierini L.M. Maxfield F.R. Aggregated LDL in contact with macrophages induces local increases in free cholesterol levels that regulate local actin polymerization.Arterioscler. Thromb. Vasc. Biol. 2009; 29: 1615-1621Crossref PubMed Scopus (33) Google Scholar, 4.Singh R.K. Barbosa-Lorenzi V.C. Lund F.W. Grosheva I. Maxfield F.R. Haka A.S. Degradation of aggregated LDL occurs in complex extracellular sub-compartments of the lysosomal synapse.J. Cell Sci. 2016; 129: 1072-1082Crossref PubMed Scopus (25) Google Scholar). In and a was for in the This was to the and the with was These for the to the with This was by the of in the of neutral to not with the was and by the of in the of the extracellular we and the of agLDL within the cell the of agLDL and the from the to extracellular agLDL We this as a of agLDL was of two a by was LDL becomes in ceramide during (5.Schissel S.L. Tweedie-Hardman J. Rapp J.H. Graham G. Williams K.J. Tabas I. Rabbit aorta and human atherosclerotic lesions hydrolyze the sphingomyelin of retained low-density lipoprotein. Proposed role for arterial-wall sphingomyelinase in subendothelial retention and aggregation of atherogenic lipoproteins.J. Clin. Invest. 1996; 98: 1455-1464Crossref PubMed Scopus (269) Google Scholar). macrophages into contact with such ceramide, we from mice and for to and for ceramide a that for X. A.R. J. arterial through of cellular 2016; PubMed Scopus Google Scholar). We found that lesional macrophages contact ceramide, in regions to and We also macrophages that ceramide and with A of ceramide in the is likely to be lesional aggregated LDL, which is known to be in ceramide and accumulate in the of the (5.Schissel S.L. Tweedie-Hardman J. Rapp J.H. Graham G. Williams K.J. Tabas I. Rabbit aorta and human atherosclerotic lesions hydrolyze the sphingomyelin of retained low-density lipoprotein. Proposed role for arterial-wall sphingomyelinase in subendothelial retention and aggregation of atherogenic lipoproteins.J. Clin. Invest. 1996; 98: 1455-1464Crossref PubMed Scopus (269) Google Scholar, P. and 2009; PubMed Scopus Google Scholar). macrophages catabolize and this LDL, they accumulate the ceramide. SK2KO macrophages increased levels of ceramide Y. Haka A.S. Maxfield F.R. E. are not for in Biol. J. Biol. PubMed Scopus Google Scholar). with we found that SK2KO for ceramide of this a in ceramide in SK2KO compared with We have SK2KO macrophages to the role of ceramide in the response of to agLDL. is we found that other in the SK2KO such as or in the response of SK2KO to agLDL. We and SK2KO macrophages with agLDL to the effect of KO on actin polymerization. macrophages with agLDL actin polymerization at the LS but SK2KO a in actin polymerization in response to agLDL at the LS and a we to in actin polymerization in SK2KO the LS, that are local and not previously to be in SK2KO Y. Haka A.S. Maxfield F.R. E. are not for in Biol. J. Biol. PubMed Scopus Google Scholar). the role of in of actin polymerization in response to agLDL in SK2KO we in and and actin polymerization in response to agLDL. and SK2KO a of in actin polymerization as SK2KO at the LS, that of impaired actin polymerization The function of sphingosine is to sphingosine to can a of and can actin through of to and E. C. P. induces in for in the of through Cell Sci. PubMed Scopus Google Scholar, E. G. regulate actin by and in the Cell Sci. 2009; PubMed Scopus Google Scholar, C. P. regulates in PubMed Scopus Google Scholar). it that sufficient be generated within of agLDL treatment to accumulate in the to or and actin polymerization, we of the SK2KO We not a in actin polymerization in response to agLDL in KO or KO in with This that of and signaling the the SK2KO SK2KO accumulate sphingosine and Y. Haka A.S. Maxfield F.R. E. are not for in Biol. J. Biol. PubMed Scopus Google Scholar). a role for in of actin polymerization in SK2KO we and SK2KO macrophages with C16-ceramide or to agLDL with C16-ceramide to a in in macrophages to the of SK2KO in actin polymerization was at the of SK2KO macrophages with C16-ceramide not impair actin polymerization in with SK2KO macrophages This that increased ceramide impairs actin polymerization and at the LS, and effect is when ceramide is to SK2KO macrophages. These are with of actin polymerization in SK2KO macrophages due to increased levels of ceramide. we also which can and found to with C16-ceramide We have shown previously that actin polymerization at the LS is for agLDL catabolism and foam cell formation (3.Grosheva I. Haka A.S. Qin C. Pierini L.M. Maxfield F.R. Aggregated LDL in contact with macrophages induces local increases in free cholesterol levels that regulate local actin polymerization.Arterioscler. Thromb. Vasc. Biol. 2009; 29: 1615-1621Crossref PubMed Scopus (33) Google Scholar). We that actin polymerization in SK2KO macrophages may to of and foam cell formation. We macrophages with agLDL and neutral and SK2KO macrophages low levels of treatment with agLDL, SK2KO macrophages a in with macrophages in neutral as by with agLDL internalized by macrophages by SK2KO macrophages agLDL extracellular This in agLDL that extracellular in SK2KO macrophages was by These that agLDL catabolism, and foam cell formation are impaired in SK2KO macrophages when to agLDL. of actin polymerization can other mechanisms of LDL such as of aggregated low-density by PubMed Scopus Google Scholar). we of LDL in this we of agLDL. The pathway by macrophages to agLDL is an extracellular the LS of aggregated low-density by PubMed Scopus Google Scholar). to the of the of agLDL catabolism and foam cell formation in SK2KO we of and and SK2KO of in LDL was in SK2KO in with of that actin polymerization was to in SK2KO at sites of in response to and LDL These a role for in impaired agLDL catabolism and foam cell formation in SK2KO We in and SK2KO macrophage which that and regulate macrophage but are not for Cell Sci. PubMed Scopus Google Scholar). the of and SK2KO we for and in the the cell was to the This is in to of with agLDL because agLDL is on of the from the of the cell are shown for macrophages at the contact with the SK2KO macrophages a SK2KO macrophages an in cell in with macrophages SK2KO macrophages to a and a or an We the and SK2KO macrophages a in with macrophages that not the but also the of was These that SK2KO macrophages display a from macrophages. SK2KO macrophage is to that previously in which was to of RhoA Y. RhoA activity to macrophage and Cell Sci. PubMed Scopus Google Scholar). RhoA is an important of the actin Y. induces formation through ceramide role of sphingosine Biol. Cell. PubMed Scopus Google Scholar). Activation of RhoA increases and can actin polymerization during Cell Biol. 2016; PubMed Scopus Google Scholar). We that increased RhoA signaling be for of actin polymerization at the LS in SK2KO macrophages. We active RhoA in and SK2KO an We a increased RhoA activation in SK2KO macrophages compared with this not RhoA is for actin polymerization in SK2KO and SK2KO with or to RhoA levels. that RhoA was by compared with in and SK2KO macrophages for to actin in response to agLDL. and RhoA macrophages in SK2KO RhoA treatment actin polymerization at the LS in response to agLDL and These that activation of RhoA in SK2KO macrophages impaired actin polymerization at the LS in response to agLDL. In of impaired actin polymerization in response to agLDL by C16-ceramide of macrophages be by inhibition of RhoA by Rho treatment of Rho treatment was by the of Rho and SK2KO in the known to be by Rho inhibition Jones J.W. and regulate actin and cell in Cell Sci. Google Scholar) and RhoA is known to function with Rho kinase for of RhoA was with Rho kinase to local actin polymerization at the LS in SK2KO we macrophages with a Rho kinase to agLDL Rho kinase inhibition effect on at the LS in macrophages at the LS treatment local actin polymerization at the LS in SK2KO macrophages to levels and of is known to be by Rho kinase by and to and PubMed Scopus Google Scholar). of and SK2KO with to a in levels of this the of Rho kinase inhibition in be to be in SK2KO macrophages that have increased RhoA mechanisms are known to to levels of in RhoA Y. K. C. macrophages Rho GTPases and have but and Biol. PubMed Scopus Google Scholar) and through in activity of kinase or kinase and in and cell Cell Biol. PubMed Scopus Google Scholar). that increased RhoA signaling through Rho kinase is for of actin polymerization at the LS in SK2KO macrophages. of RhoA and inhibition of Rho kinase actin polymerization in SK2KO they a effect in This the of RhoA modulates actin in the of ceramide in SK2KO we actin polymerization in response to agLDL in macrophages with wild-type or active actin in response to agLDL and actin polymerization, this was not but actin polymerization at the LS in response to agLDL and These that activation of RhoA can actin polymerization at the LS in response to agLDL, in the of ceramide. polymerization promotes agLDL catabolism and foam cell we activation of RhoA impair foam cell formation in response to agLDL. agLDL to accumulate of or These show that activation of RhoA of ceramide can impair actin polymerization and foam cell formation in response to agLDL. We have previously that lysosome exocytosis occurs at the LS to agLDL catabolism (2.Haka A.S. Grosheva I. Chiang E. Buxbaum A.R. Baird B.A. Pierini L.M. Maxfield F.R. Macrophages create an acidic extracellular hydrolytic compartment to digest aggregated lipoproteins.Mol. Biol. Cell. 2009; 20: 4932-4940Crossref PubMed Scopus (88) Google Scholar). which at an acidic pH occurs at the we generation of ceramide in the LS during agLDL catabolism actin polymerization at the this to ceramide from agLDL have to be of to the we into LDL to aggregation and the agLDL with wild-type macrophages. Macrophages with agLDL with of as was in macrophages with in the agLDL, of was as as This that ceramide can the cell during agLDL A likely of ceramide at the LS is generated by by lysosome and of sphingomyelin in agLDL. we actin polymerization at the LS in macrophages from or KO mice in acid and macrophages a in actin polymerization at the LS macrophages and These a role for and ceramide in actin polymerization at the this and to the role of in this we wild-type macrophages with or an to ceramide generation at the LS from agLDL is a that in the acidic compartment and induces of K. K. The of lysosomal sphingomyelinase in human PubMed Scopus Google Scholar, K. of acid sphingomyelinase and in the of the PubMed Scopus Google Scholar). of a in actin polymerization at the LS and inhibition of and Rho kinase and treatment not actin polymerization levels for and These that ceramide is not generated during agLDL catabolism, RhoA signaling is not and actin polymerization at the LS is These are with a role for ceramide in the inhibition of actin polymerization at the LS during agLDL catabolism through a RhoA/Rho A event in the of is the retention of LDL in the (1.Tabas I. Williams K.J. Boren J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications.Circulation. 2007; 116: 1832-1844Crossref PubMed Scopus (977) Google Scholar). This LDL is aggregated and to the extracellular it be internalized by standard endocytic Macrophages use a the LS, by local actin polymerization, to digest this LDL to This to foam cell a process to the of are to cell which cellular cholesterol into the of regulatory mechanisms that can the of foam cell formation is of we a RhoA/Rho regulatory by ceramide, which actin polymerization and the of agLDL catabolism and foam cell formation in response to agLDL. We also show that the process of agLDL catabolism can ceramide generation from agLDL, and this can actin polymerization through RhoA/Rho This is likely to a role in as ceramide is in the microenvironment and in lesional LDL (5.Schissel S.L. Tweedie-Hardman J. Rapp J.H. Graham G. Williams K.J. Tabas I. Rabbit aorta and human atherosclerotic lesions hydrolyze the sphingomyelin of retained low-density lipoprotein. Proposed role for arterial-wall sphingomyelinase in subendothelial retention and aggregation of atherogenic lipoproteins.J. 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G. of acid sphingomyelinase in macrophages with low-density lipoprotein and LDL role in and PubMed Scopus Google Scholar). ceramide can a role in studies have of ceramide are as a such of this during plasma membrane exocytosis by to the plasma membrane can to the cell sphingomyelin in the membrane is into ceramide to ceramide-rich membrane C. C. X. E. Tabas I. Exocytosis of acid sphingomyelinase by promotes and plasma membrane Cell Biol. PubMed Scopus Google Scholar). These lesions that and they are internalized by the cell and for C. C. X. E. Tabas I. Exocytosis of acid sphingomyelinase by promotes and plasma membrane Cell Biol. PubMed Scopus Google Scholar). ceramide can a role within the cell In this we show that ceramide within the cell can actin polymerization at the LS and that activation or of RhoA/Rho kinase is sufficient to actin polymerization at the LS Ceramide is also generated by agLDL catabolism at the LS ceramide can local actin polymerization at the LS, through a RhoA/Rho Ceramide generated at the LS may and have shown that ceramide an of in a K. P. of ceramide with of PubMed Scopus Google Scholar). we to show that in kinase actin polymerization in the we unable to ceramide generated at the LS act to the in be for macrophage and the agLDL catabolism and other critical such as to from ceramide-rich C. C. X. E. Tabas I. Exocytosis of acid sphingomyelinase by promotes and plasma membrane Cell Biol. PubMed Scopus Google cell to extracellular and cell activation of RhoA is known to of Rac/Cdc42 at Rho in cell Cell Biol. PubMed Scopus Google Scholar). studies on the of such local at the This characterized the effect of ceramide on inhibition of agLDL catabolism and foam cell which may be a effect on RhoA activation may a pathway that may be and activation of RhoA was shown to in mice K. C. Boren J. increases macrophage cholesterol and in PubMed Scopus Google Scholar). was ceramide is a critical of cell The of macrophages to in atherosclerotic lesions is This the that ceramide be cell in atherosclerotic lesions, a process that Increased RhoA activation in atherosclerotic lesions in K. Y. Y. Y. RhoA and in the atherosclerotic lesions of Thromb. 2009; PubMed Scopus Google Scholar), and RhoA activity is known to impair Rac/Cdc42 activation during Cell Biol. 2016; PubMed Scopus Google Scholar). activation of RhoA by ceramide in atherosclerotic lesions impair macrophage and from the to and from are to the of studies are to the role of signaling in macrophage during The at the and at for and The of and of for The of and of for critical of the aggregated LDL actin lysosomal sphingomyelinase lysosomal synapse sphingosine kinase sphingosine kinase 2 secretory sphingomyelinase

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