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Dystrophin deficiency reduces atherosclerotic plaque development in ApoE- mice.

Shami A, Knutsson A, Dunér P, Rauch U, Bengtsson E, Tengryd C, Murugesan V, Durbeej M, Gonçalves I, Nilsson J, Hultgårdh-Nilsson A - Sci Rep (2015)

Bottom Line: Dystrophin of the dystrophin-glycoprotein complex connects the actin cytoskeleton to basement membranes and loss of dystrophin results in Duchenne muscular dystrophy.ApoE- mdx mice were also found to have a reduced fraction of CD3(+) T cells in the spleen and lower levels of cytokines and monocytes in the circulation.The present study is the first to demonstrate a role for dystrophin in atherosclerosis and unexpectedly shows that this primarily involves immune cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Medical Science, Lund University, Lund, Sweden.

ABSTRACT
Dystrophin of the dystrophin-glycoprotein complex connects the actin cytoskeleton to basement membranes and loss of dystrophin results in Duchenne muscular dystrophy. We have previously shown injury-induced neointima formation of the carotid artery in mice with the mdx mutation (causing dystrophin deficiency) to be increased. To investigate the role of dystrophin in intimal recruitment of smooth muscle cells (SMCs) that maintains plaque stability in atherosclerosis we applied a shear stress-modifying cast around the carotid artery of apolipoprotein E (ApoE)- mice with and without the mdx mutation. The cast induces formation of atherosclerotic plaques of inflammatory and SMC-rich/fibrous phenotypes in regions of low and oscillatory shear stress, respectively. Unexpectedly, presence of the mdx mutation markedly reduced the development of the inflammatory low shear stress plaques. Further characterization of the low shear stress plaques in ApoE- mdx mice demonstrated reduced infiltration of CD3(+) T cells, less laminin and a higher SMC content. ApoE- mdx mice were also found to have a reduced fraction of CD3(+) T cells in the spleen and lower levels of cytokines and monocytes in the circulation. The present study is the first to demonstrate a role for dystrophin in atherosclerosis and unexpectedly shows that this primarily involves immune cells.

No MeSH data available.


Related in: MedlinePlus

Lack of dystrophin in high fat diet fed apoE mice results in decreased T cells and monocytes.Quantification of frequencies of CD3+ splenocytes (a), IFNγ+ (b), IL5+ (c), IL-17+ (d) and FoxP3+ CD25+ (e) among T cells, and CD115+ (f) and Ly6CHigh CD115+ (g) among PBMCs with comparisons made through the Mann-Whitney U test.
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f5: Lack of dystrophin in high fat diet fed apoE mice results in decreased T cells and monocytes.Quantification of frequencies of CD3+ splenocytes (a), IFNγ+ (b), IL5+ (c), IL-17+ (d) and FoxP3+ CD25+ (e) among T cells, and CD115+ (f) and Ly6CHigh CD115+ (g) among PBMCs with comparisons made through the Mann-Whitney U test.

Mentions: To determine if the reduced accumulation of CD3+ T cells in atherosclerotic lesions of ApoE/mdx mice reflected a general effect of dystrophin deficiency on the immune system we analysed T cell and monocyte populations in the spleen and in the circulation. ApoE/mdx mice were found to have a lower fraction of CD3+ cells in spleen (Fig. 5a). The fraction of both CD3+ CD4+ and CD3+ CD4− T cells were reduced in ApoE/mdx as compared with in ApoE mice (9.7 (8.9–10.5)% versus 16.2 (11.9–18.4)%, p = 0.0006) and 21.0 (19.0–23.2)% versus 25.1 (22.5–29.5) %, p = 0.02; respectively). Further characterization of the CD4+ T cells revealed decreased IFNγ+ T cells, but increased IL5+ T cells in ApoE/mdx mice, whereas Tregs (CD25+ FoxP3+) or IL17+ CD3+ cells did not differ between ApoE/mdx mice or ApoE mice (Fig. 5b–e). In addition, ApoE/mdx mice displayed a lower fraction of monocytes in blood, as well as decreased inflammatory Ly6cHigh monocytes (Fig. 5f–g).


Dystrophin deficiency reduces atherosclerotic plaque development in ApoE- mice.

Shami A, Knutsson A, Dunér P, Rauch U, Bengtsson E, Tengryd C, Murugesan V, Durbeej M, Gonçalves I, Nilsson J, Hultgårdh-Nilsson A - Sci Rep (2015)

Lack of dystrophin in high fat diet fed apoE mice results in decreased T cells and monocytes.Quantification of frequencies of CD3+ splenocytes (a), IFNγ+ (b), IL5+ (c), IL-17+ (d) and FoxP3+ CD25+ (e) among T cells, and CD115+ (f) and Ly6CHigh CD115+ (g) among PBMCs with comparisons made through the Mann-Whitney U test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4561962&req=5

f5: Lack of dystrophin in high fat diet fed apoE mice results in decreased T cells and monocytes.Quantification of frequencies of CD3+ splenocytes (a), IFNγ+ (b), IL5+ (c), IL-17+ (d) and FoxP3+ CD25+ (e) among T cells, and CD115+ (f) and Ly6CHigh CD115+ (g) among PBMCs with comparisons made through the Mann-Whitney U test.
Mentions: To determine if the reduced accumulation of CD3+ T cells in atherosclerotic lesions of ApoE/mdx mice reflected a general effect of dystrophin deficiency on the immune system we analysed T cell and monocyte populations in the spleen and in the circulation. ApoE/mdx mice were found to have a lower fraction of CD3+ cells in spleen (Fig. 5a). The fraction of both CD3+ CD4+ and CD3+ CD4− T cells were reduced in ApoE/mdx as compared with in ApoE mice (9.7 (8.9–10.5)% versus 16.2 (11.9–18.4)%, p = 0.0006) and 21.0 (19.0–23.2)% versus 25.1 (22.5–29.5) %, p = 0.02; respectively). Further characterization of the CD4+ T cells revealed decreased IFNγ+ T cells, but increased IL5+ T cells in ApoE/mdx mice, whereas Tregs (CD25+ FoxP3+) or IL17+ CD3+ cells did not differ between ApoE/mdx mice or ApoE mice (Fig. 5b–e). In addition, ApoE/mdx mice displayed a lower fraction of monocytes in blood, as well as decreased inflammatory Ly6cHigh monocytes (Fig. 5f–g).

Bottom Line: Dystrophin of the dystrophin-glycoprotein complex connects the actin cytoskeleton to basement membranes and loss of dystrophin results in Duchenne muscular dystrophy.ApoE- mdx mice were also found to have a reduced fraction of CD3(+) T cells in the spleen and lower levels of cytokines and monocytes in the circulation.The present study is the first to demonstrate a role for dystrophin in atherosclerosis and unexpectedly shows that this primarily involves immune cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Medical Science, Lund University, Lund, Sweden.

ABSTRACT
Dystrophin of the dystrophin-glycoprotein complex connects the actin cytoskeleton to basement membranes and loss of dystrophin results in Duchenne muscular dystrophy. We have previously shown injury-induced neointima formation of the carotid artery in mice with the mdx mutation (causing dystrophin deficiency) to be increased. To investigate the role of dystrophin in intimal recruitment of smooth muscle cells (SMCs) that maintains plaque stability in atherosclerosis we applied a shear stress-modifying cast around the carotid artery of apolipoprotein E (ApoE)- mice with and without the mdx mutation. The cast induces formation of atherosclerotic plaques of inflammatory and SMC-rich/fibrous phenotypes in regions of low and oscillatory shear stress, respectively. Unexpectedly, presence of the mdx mutation markedly reduced the development of the inflammatory low shear stress plaques. Further characterization of the low shear stress plaques in ApoE- mdx mice demonstrated reduced infiltration of CD3(+) T cells, less laminin and a higher SMC content. ApoE- mdx mice were also found to have a reduced fraction of CD3(+) T cells in the spleen and lower levels of cytokines and monocytes in the circulation. The present study is the first to demonstrate a role for dystrophin in atherosclerosis and unexpectedly shows that this primarily involves immune cells.

No MeSH data available.


Related in: MedlinePlus