Dystrophin deficiency reduces atherosclerotic plaque development in ApoE-null mice.
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)-null 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-null mdx mice demonstrated reduced infiltration of CD3(+) T cells, less laminin and a higher SMC content. ApoE-null 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.
Department of Experimental Medical Science, Lund University, Lund, Sweden.
Annelie
A
Shami
Department of Experimental Medical Science, Lund University, Lund, Sweden.
Anki
A
Knutsson
Department of Clinical Sciences, Lund University, Malmoe, Sweden.
Pontus
P
Dunér
Department of Experimental Medical Science, Lund University, Lund, Sweden.
Uwe
U
Rauch
Department of Clinical Sciences, Lund University, Malmoe, Sweden.
Eva
E
Bengtsson
Department of Clinical Sciences, Lund University, Malmoe, Sweden.
Christoffer
C
Tengryd
Department of Experimental Medical Science, Lund University, Lund, Sweden.
Vignesh
V
Murugesan
Department of Experimental Medical Science, Lund University, Lund, Sweden.
Madeleine
M
Durbeej
Department of Clinical Sciences, Lund University, Malmoe, Sweden.|Department of Cardiology, Clinical Sciences, Lund University, Malmoe, Sweden.
Isabel
I
Gonçalves
Department of Clinical Sciences, Lund University, Malmoe, Sweden.
Jan
J
Nilsson
Department of Experimental Medical Science, Lund University, Lund, Sweden.
Anna
A
Hultgårdh-Nilsson
D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics* / Q000473:pathology*; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D016189:Dystrophin / Q000172:deficiency*; D015870:Gene Expression; D007797:Laminin / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000473:pathology; D058226:Plaque, Atherosclerotic / Q000235:genetics* / Q000473:pathology*; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D013314:Stress, Mechanical; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
D001057:Apolipoproteins E; D016207:Cytokines; D016189:Dystrophin; D007797:Laminin