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Foam cell-derived 4-hydroxynonenal induces endothelial cell senescence in a TXNIP-dependent manner.

Riahi Y, Kaiser N, Cohen G, Abd-Elrahman I, Blum G, Shapira OM, Koler T, Simionescu M, Sima AV, Zarkovic N, Zarkovic K, Orioli M, Aldini G, Cerasi E, Leibowitz G, Sasson S - J. Cell. Mol. Med. (2015)

Bottom Line: This senescent phenotype was mediated by 4-hydroxnonenal (4-HNE), a lipid peroxidation product secreted from foam cells; scavenging of 4-HNE in the co-culture medium blunted this effect.Molecular manipulation of TXNIP expression confirmed its involvement in foam cell-induced senescence.Collectively, these findings suggest that foam cell-released 4-HNE activates PPARδ in VEC, leading to increased TXNIP expression and consequently to senescence.

View Article: PubMed Central - PubMed

Affiliation: Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel.

No MeSH data available.


Related in: MedlinePlus

Suggested model of foam cell-induced VEC senescence. Foam cell-derived lipid peroxidation products, among which 4-HNE, reach VEC and activate PPARδ and subsequently increase the expression of TXNIP which augments oxidative stress and VEC senescence.
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fig07: Suggested model of foam cell-induced VEC senescence. Foam cell-derived lipid peroxidation products, among which 4-HNE, reach VEC and activate PPARδ and subsequently increase the expression of TXNIP which augments oxidative stress and VEC senescence.

Mentions: Cellular senescence has been linked to endothelial cell dysfunction and atherosclerosis 14,63. In the present study we investigated the mechanism involved in foam cell-induced VEC senescence. Using a co-culture system, in which VEC were exposed on the apical side to soluble factors released by foam cells 23,25, we found that the latter produced soluble factors that promoted SIPS in VEC. Our findings provide an important insight into the signal transduction pathway that culminated in endothelial cell senescence: foam cells derived from macrophages following exposure to OxLDL secreted lipid peroxidation products, including the nucleophilic aldehyde 4-HNE. The latter interacted with VEC and activated the nuclear factor PPARδ, which transactivated the TXNIP promoter. Consequently, TXNIP expression was increased, promoting senescence in the endothelial cells (see model in Fig.7).


Foam cell-derived 4-hydroxynonenal induces endothelial cell senescence in a TXNIP-dependent manner.

Riahi Y, Kaiser N, Cohen G, Abd-Elrahman I, Blum G, Shapira OM, Koler T, Simionescu M, Sima AV, Zarkovic N, Zarkovic K, Orioli M, Aldini G, Cerasi E, Leibowitz G, Sasson S - J. Cell. Mol. Med. (2015)

Suggested model of foam cell-induced VEC senescence. Foam cell-derived lipid peroxidation products, among which 4-HNE, reach VEC and activate PPARδ and subsequently increase the expression of TXNIP which augments oxidative stress and VEC senescence.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4549039&req=5

fig07: Suggested model of foam cell-induced VEC senescence. Foam cell-derived lipid peroxidation products, among which 4-HNE, reach VEC and activate PPARδ and subsequently increase the expression of TXNIP which augments oxidative stress and VEC senescence.
Mentions: Cellular senescence has been linked to endothelial cell dysfunction and atherosclerosis 14,63. In the present study we investigated the mechanism involved in foam cell-induced VEC senescence. Using a co-culture system, in which VEC were exposed on the apical side to soluble factors released by foam cells 23,25, we found that the latter produced soluble factors that promoted SIPS in VEC. Our findings provide an important insight into the signal transduction pathway that culminated in endothelial cell senescence: foam cells derived from macrophages following exposure to OxLDL secreted lipid peroxidation products, including the nucleophilic aldehyde 4-HNE. The latter interacted with VEC and activated the nuclear factor PPARδ, which transactivated the TXNIP promoter. Consequently, TXNIP expression was increased, promoting senescence in the endothelial cells (see model in Fig.7).

Bottom Line: This senescent phenotype was mediated by 4-hydroxnonenal (4-HNE), a lipid peroxidation product secreted from foam cells; scavenging of 4-HNE in the co-culture medium blunted this effect.Molecular manipulation of TXNIP expression confirmed its involvement in foam cell-induced senescence.Collectively, these findings suggest that foam cell-released 4-HNE activates PPARδ in VEC, leading to increased TXNIP expression and consequently to senescence.

View Article: PubMed Central - PubMed

Affiliation: Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel.

No MeSH data available.


Related in: MedlinePlus