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Endothelial and macrophage-specific deficiency of P38α MAPK does not affect the pathogenesis of atherosclerosis in ApoE-/- mice.

Kardakaris R, Gareus R, Xanthoulea S, Pasparakis M - PLoS ONE (2011)

Bottom Line: The p38α Mitogen-Activated Protein Kinase (MAPK) regulates stress- and inflammation-induced cellular responses.Surprisingly, although p38α-deficiency strongly attenuated oxidized LDL-induced expression of molecules responsible for monocyte recruitment in endothelial cell cultures in vitro, endothelial-specific p38α ablation in vivo did not affect atherosclerosis development.Similarly, macrophage specific deletion of p38α did not affect atherosclerotic plaque development in ApoE(-/-) mice.

View Article: PubMed Central - PubMed

Affiliation: Centre for Molecular Medicine, Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.

ABSTRACT

Background: The p38α Mitogen-Activated Protein Kinase (MAPK) regulates stress- and inflammation-induced cellular responses. Factors implicated in the development of atherosclerosis including modified low-density lipoprotein (LDL), cytokines and even shear stress induce p38 activation in endothelial cells and macrophages, which may be important for plaque formation. This study investigates the effects of endothelial- and macrophage-specific deficiency of p38α in atherosclerosis development, in Apolipoprotein E deficient (ApoE(-/-)) mice.

Methodology/principal findings: ApoE(-/-) mice with macrophage or endothelial cell-specific p38α deficiency were fed a high cholesterol diet (HCD) for 10 weeks and atherosclerosis development was assessed by histological and molecular methods. Surprisingly, although p38α-deficiency strongly attenuated oxidized LDL-induced expression of molecules responsible for monocyte recruitment in endothelial cell cultures in vitro, endothelial-specific p38α ablation in vivo did not affect atherosclerosis development. Similarly, macrophage specific deletion of p38α did not affect atherosclerotic plaque development in ApoE(-/-) mice.

Conclusions: Although previous studies implicated p38α signaling in atherosclerosis, our in vivo experiments suggest that p38α function in endothelial cells and macrophages does not play an important role in atherosclerotic plaque formation in ApoE deficient mice.

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Similar plaque characteristics, cytokine, chemokine and adhesion molecule expression in p38αMY-KO/ApoE−/− and ApoE−/− mice.Staining and quantification at the aortic sinus of p38αMY-KO/ApoE−/− and ApoE−/− mice for: (A) Collagen content, Masson Trichrome staining (blue fibres, indicated by arrows), (B) Foam cell content, MOMA2 staining (red, indicated by arrows), (C) Necrotic core area, clear areas in lesions that did not stain for toluidine blue (nec = necrosis). (D) Relative mRNA levels of adhesion molecules, pro-inflammatory cytokines and chemokines (left to right) of aortal arches from p38αMY-KO/ApoE−/− and ApoE−/− mice after 10 weeks on HCD. P38αMY-KO/ApoE−/− females, n = 8; ApoE−/− females, n = 9. Scale bar 50 µm. Error bars represent SD.
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pone-0021055-g005: Similar plaque characteristics, cytokine, chemokine and adhesion molecule expression in p38αMY-KO/ApoE−/− and ApoE−/− mice.Staining and quantification at the aortic sinus of p38αMY-KO/ApoE−/− and ApoE−/− mice for: (A) Collagen content, Masson Trichrome staining (blue fibres, indicated by arrows), (B) Foam cell content, MOMA2 staining (red, indicated by arrows), (C) Necrotic core area, clear areas in lesions that did not stain for toluidine blue (nec = necrosis). (D) Relative mRNA levels of adhesion molecules, pro-inflammatory cytokines and chemokines (left to right) of aortal arches from p38αMY-KO/ApoE−/− and ApoE−/− mice after 10 weeks on HCD. P38αMY-KO/ApoE−/− females, n = 8; ApoE−/− females, n = 9. Scale bar 50 µm. Error bars represent SD.

Mentions: To address the potential role of macrophage p38α in atherosclerosis, we placed groups of male and female p38MY-KO/ApoE−/− and their ApoE−/− littermates on HCD for 10 weeks, starting from 6–8 weeks of age. Analysis of bodyweight and cholesterol levels, before and after the HCD treatment, revealed no differences between the two genotypes, which showed similarly increased cholesterol levels and body weight after HCD feeding (Figure S2B). After 10 weeks on HCD, mice were sacrificed, and atherosclerotic lesion development was assessed in the whole aorta by en face staining with Sudan IV (Figure 4C), but also at the aortic sinuses (Figure 4D). This analysis did not reveal differences in lesion size between p38αMY-KO/ApoE−/− and their ApoE−/− littermates, either in the whole aorta or in the aortic sinuses. Quantification of collagen content, foam cell formation and necrotic area also did not reveal any differences between the two genotypes (Figure 5A, B and C, respectively). Taken together, our experiments showed that macrophage p38α deficiency did not affect atherosclerotic plaque development in ApoE−/− mice as assessed by quantification of lesion size, collagen and macrophage content and necrotic core area. These findings are in contrast to the results reported by Seimon and colleagues, who found increased lesional necrosis and decreased collagen content in atherosclerotic plaques from p38αMY-KO/ApoE−/−, compared to ApoE−/− controls [8].


Endothelial and macrophage-specific deficiency of P38α MAPK does not affect the pathogenesis of atherosclerosis in ApoE-/- mice.

Kardakaris R, Gareus R, Xanthoulea S, Pasparakis M - PLoS ONE (2011)

Similar plaque characteristics, cytokine, chemokine and adhesion molecule expression in p38αMY-KO/ApoE−/− and ApoE−/− mice.Staining and quantification at the aortic sinus of p38αMY-KO/ApoE−/− and ApoE−/− mice for: (A) Collagen content, Masson Trichrome staining (blue fibres, indicated by arrows), (B) Foam cell content, MOMA2 staining (red, indicated by arrows), (C) Necrotic core area, clear areas in lesions that did not stain for toluidine blue (nec = necrosis). (D) Relative mRNA levels of adhesion molecules, pro-inflammatory cytokines and chemokines (left to right) of aortal arches from p38αMY-KO/ApoE−/− and ApoE−/− mice after 10 weeks on HCD. P38αMY-KO/ApoE−/− females, n = 8; ApoE−/− females, n = 9. Scale bar 50 µm. Error bars represent SD.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3111465&req=5

pone-0021055-g005: Similar plaque characteristics, cytokine, chemokine and adhesion molecule expression in p38αMY-KO/ApoE−/− and ApoE−/− mice.Staining and quantification at the aortic sinus of p38αMY-KO/ApoE−/− and ApoE−/− mice for: (A) Collagen content, Masson Trichrome staining (blue fibres, indicated by arrows), (B) Foam cell content, MOMA2 staining (red, indicated by arrows), (C) Necrotic core area, clear areas in lesions that did not stain for toluidine blue (nec = necrosis). (D) Relative mRNA levels of adhesion molecules, pro-inflammatory cytokines and chemokines (left to right) of aortal arches from p38αMY-KO/ApoE−/− and ApoE−/− mice after 10 weeks on HCD. P38αMY-KO/ApoE−/− females, n = 8; ApoE−/− females, n = 9. Scale bar 50 µm. Error bars represent SD.
Mentions: To address the potential role of macrophage p38α in atherosclerosis, we placed groups of male and female p38MY-KO/ApoE−/− and their ApoE−/− littermates on HCD for 10 weeks, starting from 6–8 weeks of age. Analysis of bodyweight and cholesterol levels, before and after the HCD treatment, revealed no differences between the two genotypes, which showed similarly increased cholesterol levels and body weight after HCD feeding (Figure S2B). After 10 weeks on HCD, mice were sacrificed, and atherosclerotic lesion development was assessed in the whole aorta by en face staining with Sudan IV (Figure 4C), but also at the aortic sinuses (Figure 4D). This analysis did not reveal differences in lesion size between p38αMY-KO/ApoE−/− and their ApoE−/− littermates, either in the whole aorta or in the aortic sinuses. Quantification of collagen content, foam cell formation and necrotic area also did not reveal any differences between the two genotypes (Figure 5A, B and C, respectively). Taken together, our experiments showed that macrophage p38α deficiency did not affect atherosclerotic plaque development in ApoE−/− mice as assessed by quantification of lesion size, collagen and macrophage content and necrotic core area. These findings are in contrast to the results reported by Seimon and colleagues, who found increased lesional necrosis and decreased collagen content in atherosclerotic plaques from p38αMY-KO/ApoE−/−, compared to ApoE−/− controls [8].

Bottom Line: The p38α Mitogen-Activated Protein Kinase (MAPK) regulates stress- and inflammation-induced cellular responses.Surprisingly, although p38α-deficiency strongly attenuated oxidized LDL-induced expression of molecules responsible for monocyte recruitment in endothelial cell cultures in vitro, endothelial-specific p38α ablation in vivo did not affect atherosclerosis development.Similarly, macrophage specific deletion of p38α did not affect atherosclerotic plaque development in ApoE(-/-) mice.

View Article: PubMed Central - PubMed

Affiliation: Centre for Molecular Medicine, Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.

ABSTRACT

Background: The p38α Mitogen-Activated Protein Kinase (MAPK) regulates stress- and inflammation-induced cellular responses. Factors implicated in the development of atherosclerosis including modified low-density lipoprotein (LDL), cytokines and even shear stress induce p38 activation in endothelial cells and macrophages, which may be important for plaque formation. This study investigates the effects of endothelial- and macrophage-specific deficiency of p38α in atherosclerosis development, in Apolipoprotein E deficient (ApoE(-/-)) mice.

Methodology/principal findings: ApoE(-/-) mice with macrophage or endothelial cell-specific p38α deficiency were fed a high cholesterol diet (HCD) for 10 weeks and atherosclerosis development was assessed by histological and molecular methods. Surprisingly, although p38α-deficiency strongly attenuated oxidized LDL-induced expression of molecules responsible for monocyte recruitment in endothelial cell cultures in vitro, endothelial-specific p38α ablation in vivo did not affect atherosclerosis development. Similarly, macrophage specific deletion of p38α did not affect atherosclerotic plaque development in ApoE(-/-) mice.

Conclusions: Although previous studies implicated p38α signaling in atherosclerosis, our in vivo experiments suggest that p38α function in endothelial cells and macrophages does not play an important role in atherosclerotic plaque formation in ApoE deficient mice.

Show MeSH
Related in: MedlinePlus