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Impact of oxLDL on Cholesterol-Rich Membrane Rafts.

Levitan I, Shentu TP - J Lipids (2011)

Bottom Line: However, the impact of the lipoproteins on the structure, integrity and cholesterol composition of these domains is not well understood.More specifically, we discuss three major criteria for the impact of oxLDL on membrane rafts: distribution of different membrane raft markers, changes in membrane cholesterol composition, and changes in lipid packing of different membrane domains.We also propose a model to reconcile the controversy regarding the relationship between oxLDL, membrane cholesterol, and the integrity of cholesterol-rich membrane domains.

View Article: PubMed Central - PubMed

Affiliation: Section of Pulmonary, Critical Care and Sleep Medicine, College of Medicine, University of Illinois at Chicago, 840 South Wood Street, Chicago, IL 60612, USA.

ABSTRACT
Numerous studies have demonstrated that cholesterol-rich membrane rafts play critical roles in multiple cellular functions. However, the impact of the lipoproteins on the structure, integrity and cholesterol composition of these domains is not well understood. This paper focuses on oxidized low-density lipoproteins (oxLDLs) that are strongly implicated in the development of the cardiovascular disease and whose impact on membrane cholesterol and on membrane rafts has been highly controversial. More specifically, we discuss three major criteria for the impact of oxLDL on membrane rafts: distribution of different membrane raft markers, changes in membrane cholesterol composition, and changes in lipid packing of different membrane domains. We also propose a model to reconcile the controversy regarding the relationship between oxLDL, membrane cholesterol, and the integrity of cholesterol-rich membrane domains.

No MeSH data available.


Related in: MedlinePlus

oxLDL and cholesterol depletion have similar effects on realignment of endothelial cells in the direction of the flow. Left column: typical images of control, oxLDL-treated cells (10 μg/mL oxLDL, 1 h), and MβCD-treated cells (5 mM, 1 h) exposed to 10 dyn/cm2 for 12 hours. Right column: typical images of F-actin structure in the same cell populations. Arrow indicates the direction of flow. Adapted from [24].
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fig4: oxLDL and cholesterol depletion have similar effects on realignment of endothelial cells in the direction of the flow. Left column: typical images of control, oxLDL-treated cells (10 μg/mL oxLDL, 1 h), and MβCD-treated cells (5 mM, 1 h) exposed to 10 dyn/cm2 for 12 hours. Right column: typical images of F-actin structure in the same cell populations. Arrow indicates the direction of flow. Adapted from [24].

Mentions: As described above, earlier studies by Blair et al. [21] showed that oxLDL-induced inhibition of endothelial nitric synthase (eNOS) can be simulated by MβCD-induced cholesterol depletion and abrogated by maintaining cellular cholesterol at a constant level [35]. Similarly, oxPAPC-induced production of an inflammatory cytokine Interleukin-8 was also simulated by MβCD-cholesterol depletion and prevented by cholesterol loading [42]. Furthermore, Yeh et al. [42] showed that oxPAPC also results in a sustained activation of sterol regulatory element-binding protein (SREBP) and induction of SRBEP-targeted genes (LDLR and HMG CoA synthase). Since it is well known that SREBPs are regulated by the level of cellular cholesterol and activated by cholesterol depletion [71], the ability of oxPAPC to activate SREBP is consistent with the observation that oxPAPC induces cholesterol depletion. More recently, our studies have shown that multiple effects of oxLDL on endothelial biomechanical properties can also be simulated by cholesterol depletion. First, we have shown that exposure to oxLDL and depletion of membrane cholesterol result in an increase in endothelial stiffness, as estimated by measuring progressive membrane deformation in response to negative pressure [22, 72] or by atomic force microscopy [25]. The same correlation was observed also for the ability of the cells to generate force on the cell-substrate interface [22, 25], to form endothelial networks in 3D collagen gels [22, 25] and to realign in the direction of the flow ([24], Figure 4). Furthermore, the similarities between the effects of oxLDL and MβCD on endothelial realignment in the direction of the flow are apparent both on the level of single cells and of individual F-actin fibers ([24], Figure 4). A correlation between the effects of oxLDL and cholesterol depletion across an array of different cellular functions suggests that there is a common mechanistic denominator. However, it is also possible that the common denominator is not cholesterol depletion but rather a downstream step that can be activated by both oxLDL and by cholesterol depletion independently. To address this possibility, we tested whether the effects of oxLDL can be reversed by increasing the level of membrane cholesterol. Indeed, our further studies have shown that all of the effects of oxLDL on endothelial biomechanical properties could be reversed by supplying the cells with a surplus of cholesterol either by sequential exposing the cells to acLDL [24] or by sequentially exposure to oxLDL and then to MβCD-cholesterol [25]. These observations indicate that oxLDL-induced effects on endothelial biomechanical properties are cholesterol dependent. It is important to note that enriching endothelial cells with cholesterol in the absence of oxLDL had no effect on endothelial biomechanics [25, 72] indicating that the reversibility is not a result of simple cancellation of the two opposite effects. Thus, multiple studies show a remarkable similarity between the effects of oxLDL and of MβCD on endothelial properties. In contrast, we found no similarities between the effects on oxLDL and SM hydrolysis on endothelial biomechanics suggesting that these effects cannot be attributed to oxLDL-induced formation of ceramide platforms [25].


Impact of oxLDL on Cholesterol-Rich Membrane Rafts.

Levitan I, Shentu TP - J Lipids (2011)

oxLDL and cholesterol depletion have similar effects on realignment of endothelial cells in the direction of the flow. Left column: typical images of control, oxLDL-treated cells (10 μg/mL oxLDL, 1 h), and MβCD-treated cells (5 mM, 1 h) exposed to 10 dyn/cm2 for 12 hours. Right column: typical images of F-actin structure in the same cell populations. Arrow indicates the direction of flow. Adapted from [24].
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig4: oxLDL and cholesterol depletion have similar effects on realignment of endothelial cells in the direction of the flow. Left column: typical images of control, oxLDL-treated cells (10 μg/mL oxLDL, 1 h), and MβCD-treated cells (5 mM, 1 h) exposed to 10 dyn/cm2 for 12 hours. Right column: typical images of F-actin structure in the same cell populations. Arrow indicates the direction of flow. Adapted from [24].
Mentions: As described above, earlier studies by Blair et al. [21] showed that oxLDL-induced inhibition of endothelial nitric synthase (eNOS) can be simulated by MβCD-induced cholesterol depletion and abrogated by maintaining cellular cholesterol at a constant level [35]. Similarly, oxPAPC-induced production of an inflammatory cytokine Interleukin-8 was also simulated by MβCD-cholesterol depletion and prevented by cholesterol loading [42]. Furthermore, Yeh et al. [42] showed that oxPAPC also results in a sustained activation of sterol regulatory element-binding protein (SREBP) and induction of SRBEP-targeted genes (LDLR and HMG CoA synthase). Since it is well known that SREBPs are regulated by the level of cellular cholesterol and activated by cholesterol depletion [71], the ability of oxPAPC to activate SREBP is consistent with the observation that oxPAPC induces cholesterol depletion. More recently, our studies have shown that multiple effects of oxLDL on endothelial biomechanical properties can also be simulated by cholesterol depletion. First, we have shown that exposure to oxLDL and depletion of membrane cholesterol result in an increase in endothelial stiffness, as estimated by measuring progressive membrane deformation in response to negative pressure [22, 72] or by atomic force microscopy [25]. The same correlation was observed also for the ability of the cells to generate force on the cell-substrate interface [22, 25], to form endothelial networks in 3D collagen gels [22, 25] and to realign in the direction of the flow ([24], Figure 4). Furthermore, the similarities between the effects of oxLDL and MβCD on endothelial realignment in the direction of the flow are apparent both on the level of single cells and of individual F-actin fibers ([24], Figure 4). A correlation between the effects of oxLDL and cholesterol depletion across an array of different cellular functions suggests that there is a common mechanistic denominator. However, it is also possible that the common denominator is not cholesterol depletion but rather a downstream step that can be activated by both oxLDL and by cholesterol depletion independently. To address this possibility, we tested whether the effects of oxLDL can be reversed by increasing the level of membrane cholesterol. Indeed, our further studies have shown that all of the effects of oxLDL on endothelial biomechanical properties could be reversed by supplying the cells with a surplus of cholesterol either by sequential exposing the cells to acLDL [24] or by sequentially exposure to oxLDL and then to MβCD-cholesterol [25]. These observations indicate that oxLDL-induced effects on endothelial biomechanical properties are cholesterol dependent. It is important to note that enriching endothelial cells with cholesterol in the absence of oxLDL had no effect on endothelial biomechanics [25, 72] indicating that the reversibility is not a result of simple cancellation of the two opposite effects. Thus, multiple studies show a remarkable similarity between the effects of oxLDL and of MβCD on endothelial properties. In contrast, we found no similarities between the effects on oxLDL and SM hydrolysis on endothelial biomechanics suggesting that these effects cannot be attributed to oxLDL-induced formation of ceramide platforms [25].

Bottom Line: However, the impact of the lipoproteins on the structure, integrity and cholesterol composition of these domains is not well understood.More specifically, we discuss three major criteria for the impact of oxLDL on membrane rafts: distribution of different membrane raft markers, changes in membrane cholesterol composition, and changes in lipid packing of different membrane domains.We also propose a model to reconcile the controversy regarding the relationship between oxLDL, membrane cholesterol, and the integrity of cholesterol-rich membrane domains.

View Article: PubMed Central - PubMed

Affiliation: Section of Pulmonary, Critical Care and Sleep Medicine, College of Medicine, University of Illinois at Chicago, 840 South Wood Street, Chicago, IL 60612, USA.

ABSTRACT
Numerous studies have demonstrated that cholesterol-rich membrane rafts play critical roles in multiple cellular functions. However, the impact of the lipoproteins on the structure, integrity and cholesterol composition of these domains is not well understood. This paper focuses on oxidized low-density lipoproteins (oxLDLs) that are strongly implicated in the development of the cardiovascular disease and whose impact on membrane cholesterol and on membrane rafts has been highly controversial. More specifically, we discuss three major criteria for the impact of oxLDL on membrane rafts: distribution of different membrane raft markers, changes in membrane cholesterol composition, and changes in lipid packing of different membrane domains. We also propose a model to reconcile the controversy regarding the relationship between oxLDL, membrane cholesterol, and the integrity of cholesterol-rich membrane domains.

No MeSH data available.


Related in: MedlinePlus