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ApoE-/- PGC-1α-/- mice display reduced IL-18 levels and do not develop enhanced atherosclerosis.

Stein S, Lohmann C, Handschin C, Stenfeldt E, Borén J, Lüscher TF, Matter CM - PLoS ONE (2010)

Bottom Line: The PPARγ coactivator 1 alpha (Ppargc1a or PGC-1α) was identified as an important transcriptional cofactor of PPARγ and is activated by SIRT1.Despite having more macrophages and a higher ICAM-1 expression in plaques, ApoE(-/-) PGC-1α(-/-) did not display more or larger atherosclerotic plaques than their ApoE(-/-) PGC-1α(+/+) littermates.VLDL/LDL-cholesterol and triglyceride contents were also reduced.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Research, Institute of Physiology, and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.

ABSTRACT

Background: Atherosclerosis is a chronic inflammatory disease that evolves from the interaction of activated endothelial cells, macrophages, lymphocytes and modified lipoproteins (LDLs). In the last years many molecules with crucial metabolic functions have been shown to prevent important steps in the progression of atherogenesis, including peroxisome proliferator activated receptors (PPARs) and the class III histone deacetylase (HDAC) SIRT1. The PPARγ coactivator 1 alpha (Ppargc1a or PGC-1α) was identified as an important transcriptional cofactor of PPARγ and is activated by SIRT1. The aim of this study was to analyze total PGC-1α deficiency in an atherosclerotic mouse model.

Methodology/principal findings: To investigate if total PGC-1α deficiency affects atherosclerosis, we compared ApoE(-/-) PGC-1α(-/-) and ApoE(-/-) PGC-1α(+/+) mice kept on a high cholesterol diet. Despite having more macrophages and a higher ICAM-1 expression in plaques, ApoE(-/-) PGC-1α(-/-) did not display more or larger atherosclerotic plaques than their ApoE(-/-) PGC-1α(+/+) littermates. In line with the previously published phenotype of PGC-1α(-/-) mice, ApoE(-/-) PGC-1α(-/-) mice had marked reduced body, liver and epididymal white adipose tissue (WAT) weight. VLDL/LDL-cholesterol and triglyceride contents were also reduced. Aortic expression of PPARα and PPARγ, two crucial regulators for adipocyte differentiation and glucose and lipid metabolism, as well as the expression of some PPAR target genes was significantly reduced in ApoE(-/-) PGC-1α(-/-) mice. Importantly, the epididymal WAT and aortic expression of IL-18 and IL-18 plasma levels, a pro-atherosclerotic cytokine, was markedly reduced in ApoE(-/-) PGC-1α(-/-) mice.

Conclusions/significance: ApoE(-/-) PGC-1α(-/-) mice, similar as PGC-1α(-/-) mice exhibit markedly reduced total body and visceral fat weight. Since inflammation of visceral fat is a crucial trigger of atherogenesis, decreased visceral fat in PGC-1α-deficient mice may explain why these mice do not develop enhanced atherosclerosis.

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Aortic and plasma expression levels of IL-18 and CXCL16.(A) Reduced aortic mRNA expression of IL-18 and CXCL16, but no change in the expression of IFN-γ is observed in ApoE−/− PGC-1α−/− compared to ApoE−/− PGC-1α+/+ mice. n≥9 per genotype. (B) In plasma samples only IL-18, but not CXCL16 protein levels differed between ApoE−/− PGC-1α−/− and ApoE−/− PGC-1α+/+ mice. n≥10 per genotype. * p<0.05; ** p<0.01.
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pone-0013539-g007: Aortic and plasma expression levels of IL-18 and CXCL16.(A) Reduced aortic mRNA expression of IL-18 and CXCL16, but no change in the expression of IFN-γ is observed in ApoE−/− PGC-1α−/− compared to ApoE−/− PGC-1α+/+ mice. n≥9 per genotype. (B) In plasma samples only IL-18, but not CXCL16 protein levels differed between ApoE−/− PGC-1α−/− and ApoE−/− PGC-1α+/+ mice. n≥10 per genotype. * p<0.05; ** p<0.01.

Mentions: The reduced expression of IL-18 in epididymal WAT is of special interest, since ApoE−/− IL-18−/− mice develop less atherosclerosis than control ApoE−/− mice [21]. Importantly, injection of IL-18 into SCID/apoE kockout mice elevated levels of IFN-γ and scavenger receptor for phosphatidylserine and oxidized lipoprotein/CXC chemokine ligand 16 (SR-PSOX/CXCL16) in atherosclerotic lesions [22]. Measurement of these factors in aortic tissue, revealed that IL-18 and SR-PSOX/CXCL16 mRNA levels were reduced in ApoE−/− PGC-1α−/− mice, while IFN-γ expression did not differ between the two genotypes (Fig. 7A). We also quantified the amount of IL-18 and soluble SR-PSOX/CXCL16 in plasma samples. In line with the reduced expression in epididymal WAT and aortae, IL-18 protein level was also reduced in the plasma of ApoE−/− PGC-1α−/− compared to ApoE−/− PGC-1α+/+ mice (Fig. 7B). In contrast, plasma levels of secreted SR-PSOX/CXCL16 did not differ between the two genotypes (Fig. 7B).


ApoE-/- PGC-1α-/- mice display reduced IL-18 levels and do not develop enhanced atherosclerosis.

Stein S, Lohmann C, Handschin C, Stenfeldt E, Borén J, Lüscher TF, Matter CM - PLoS ONE (2010)

Aortic and plasma expression levels of IL-18 and CXCL16.(A) Reduced aortic mRNA expression of IL-18 and CXCL16, but no change in the expression of IFN-γ is observed in ApoE−/− PGC-1α−/− compared to ApoE−/− PGC-1α+/+ mice. n≥9 per genotype. (B) In plasma samples only IL-18, but not CXCL16 protein levels differed between ApoE−/− PGC-1α−/− and ApoE−/− PGC-1α+/+ mice. n≥10 per genotype. * p<0.05; ** p<0.01.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2962638&req=5

pone-0013539-g007: Aortic and plasma expression levels of IL-18 and CXCL16.(A) Reduced aortic mRNA expression of IL-18 and CXCL16, but no change in the expression of IFN-γ is observed in ApoE−/− PGC-1α−/− compared to ApoE−/− PGC-1α+/+ mice. n≥9 per genotype. (B) In plasma samples only IL-18, but not CXCL16 protein levels differed between ApoE−/− PGC-1α−/− and ApoE−/− PGC-1α+/+ mice. n≥10 per genotype. * p<0.05; ** p<0.01.
Mentions: The reduced expression of IL-18 in epididymal WAT is of special interest, since ApoE−/− IL-18−/− mice develop less atherosclerosis than control ApoE−/− mice [21]. Importantly, injection of IL-18 into SCID/apoE kockout mice elevated levels of IFN-γ and scavenger receptor for phosphatidylserine and oxidized lipoprotein/CXC chemokine ligand 16 (SR-PSOX/CXCL16) in atherosclerotic lesions [22]. Measurement of these factors in aortic tissue, revealed that IL-18 and SR-PSOX/CXCL16 mRNA levels were reduced in ApoE−/− PGC-1α−/− mice, while IFN-γ expression did not differ between the two genotypes (Fig. 7A). We also quantified the amount of IL-18 and soluble SR-PSOX/CXCL16 in plasma samples. In line with the reduced expression in epididymal WAT and aortae, IL-18 protein level was also reduced in the plasma of ApoE−/− PGC-1α−/− compared to ApoE−/− PGC-1α+/+ mice (Fig. 7B). In contrast, plasma levels of secreted SR-PSOX/CXCL16 did not differ between the two genotypes (Fig. 7B).

Bottom Line: The PPARγ coactivator 1 alpha (Ppargc1a or PGC-1α) was identified as an important transcriptional cofactor of PPARγ and is activated by SIRT1.Despite having more macrophages and a higher ICAM-1 expression in plaques, ApoE(-/-) PGC-1α(-/-) did not display more or larger atherosclerotic plaques than their ApoE(-/-) PGC-1α(+/+) littermates.VLDL/LDL-cholesterol and triglyceride contents were also reduced.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Research, Institute of Physiology, and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.

ABSTRACT

Background: Atherosclerosis is a chronic inflammatory disease that evolves from the interaction of activated endothelial cells, macrophages, lymphocytes and modified lipoproteins (LDLs). In the last years many molecules with crucial metabolic functions have been shown to prevent important steps in the progression of atherogenesis, including peroxisome proliferator activated receptors (PPARs) and the class III histone deacetylase (HDAC) SIRT1. The PPARγ coactivator 1 alpha (Ppargc1a or PGC-1α) was identified as an important transcriptional cofactor of PPARγ and is activated by SIRT1. The aim of this study was to analyze total PGC-1α deficiency in an atherosclerotic mouse model.

Methodology/principal findings: To investigate if total PGC-1α deficiency affects atherosclerosis, we compared ApoE(-/-) PGC-1α(-/-) and ApoE(-/-) PGC-1α(+/+) mice kept on a high cholesterol diet. Despite having more macrophages and a higher ICAM-1 expression in plaques, ApoE(-/-) PGC-1α(-/-) did not display more or larger atherosclerotic plaques than their ApoE(-/-) PGC-1α(+/+) littermates. In line with the previously published phenotype of PGC-1α(-/-) mice, ApoE(-/-) PGC-1α(-/-) mice had marked reduced body, liver and epididymal white adipose tissue (WAT) weight. VLDL/LDL-cholesterol and triglyceride contents were also reduced. Aortic expression of PPARα and PPARγ, two crucial regulators for adipocyte differentiation and glucose and lipid metabolism, as well as the expression of some PPAR target genes was significantly reduced in ApoE(-/-) PGC-1α(-/-) mice. Importantly, the epididymal WAT and aortic expression of IL-18 and IL-18 plasma levels, a pro-atherosclerotic cytokine, was markedly reduced in ApoE(-/-) PGC-1α(-/-) mice.

Conclusions/significance: ApoE(-/-) PGC-1α(-/-) mice, similar as PGC-1α(-/-) mice exhibit markedly reduced total body and visceral fat weight. Since inflammation of visceral fat is a crucial trigger of atherogenesis, decreased visceral fat in PGC-1α-deficient mice may explain why these mice do not develop enhanced atherosclerosis.

Show MeSH
Related in: MedlinePlus