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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

Increases in cell density and smooth muscle cells.Increased cell density (a) and smooth muscle cell content (b)—the latter as measured by the relative content of smooth muscle α-actin (α-SMA)—in low shear stress plaques from ApoE/mdx mice compared to ApoE mice. Representative α-SMA stained sections are shown in (c–f). Scale bars represents 100 μm and Mann-Whitney U test was used.
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f2: Increases in cell density and smooth muscle cells.Increased cell density (a) and smooth muscle cell content (b)—the latter as measured by the relative content of smooth muscle α-actin (α-SMA)—in low shear stress plaques from ApoE/mdx mice compared to ApoE mice. Representative α-SMA stained sections are shown in (c–f). Scale bars represents 100 μm and Mann-Whitney U test was used.

Mentions: Along with smaller size, increased cell density was found in low shear stress plaques from ApoE/mdx compared to low shear stress plaques from ApoE mice (P = 0.0231, Fig. 2a). Smooth muscle α-actin (α-SMA) immunoreactivity—primarily found in the fibrous cap—was increased in low shear stress-plaques from ApoE/mdx mice compared to plaques from the same region in ApoE mice (2.2 (0.8–4.2)% versus 8.3 (3.6–18.0)%, P = 0.0011; Fig. 2b–f). These plaques also contained increased amounts of smooth muscle myosin heavy chain (p = 0.0048, Supplementary Fig. S4), another SMC marker associated with a differentiated phenotype32. SMC content as assessed by both markers was similar in oscillatory shear stress-plaques of both genotypes. There was no difference in cell proliferation (Ki67), apoptosis (caspase-3) or in the ratios of macrophage (mac-2) or endothelial cell (CD31) immunoreactivity in either type of plaque (Supplementary Fig. S1, S5 and S6). Consequently, the increase in SMCs appears to account for the increased cell density found in low shear stress-plaques from ApoE/mdx mice.


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)

Increases in cell density and smooth muscle cells.Increased cell density (a) and smooth muscle cell content (b)—the latter as measured by the relative content of smooth muscle α-actin (α-SMA)—in low shear stress plaques from ApoE/mdx mice compared to ApoE mice. Representative α-SMA stained sections are shown in (c–f). Scale bars represents 100 μm and Mann-Whitney U test was used.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: Increases in cell density and smooth muscle cells.Increased cell density (a) and smooth muscle cell content (b)—the latter as measured by the relative content of smooth muscle α-actin (α-SMA)—in low shear stress plaques from ApoE/mdx mice compared to ApoE mice. Representative α-SMA stained sections are shown in (c–f). Scale bars represents 100 μm and Mann-Whitney U test was used.
Mentions: Along with smaller size, increased cell density was found in low shear stress plaques from ApoE/mdx compared to low shear stress plaques from ApoE mice (P = 0.0231, Fig. 2a). Smooth muscle α-actin (α-SMA) immunoreactivity—primarily found in the fibrous cap—was increased in low shear stress-plaques from ApoE/mdx mice compared to plaques from the same region in ApoE mice (2.2 (0.8–4.2)% versus 8.3 (3.6–18.0)%, P = 0.0011; Fig. 2b–f). These plaques also contained increased amounts of smooth muscle myosin heavy chain (p = 0.0048, Supplementary Fig. S4), another SMC marker associated with a differentiated phenotype32. SMC content as assessed by both markers was similar in oscillatory shear stress-plaques of both genotypes. There was no difference in cell proliferation (Ki67), apoptosis (caspase-3) or in the ratios of macrophage (mac-2) or endothelial cell (CD31) immunoreactivity in either type of plaque (Supplementary Fig. S1, S5 and S6). Consequently, the increase in SMCs appears to account for the increased cell density found in low shear stress-plaques from ApoE/mdx mice.

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