Fasudil Decreases Lesion Burden in a Murine Model of Cerebral Cavernous Malformation Disease
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- David A. McDonald
- From the Molecular Genetics and Microbiology Department (D.A. McDonald, D.A. Marchuk), Duke University Medical Center, Durham, NC; the University of Chicago Medical Center (C.S., R.S., F.L., I.A.A.), Biological Sciences Division, University of Chicago, Chicago, IL; and the Department of Medicine (R.A.S., M.H.G.), University of California, San Diego, San Diego, CA.
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- Changbin Shi
- From the Molecular Genetics and Microbiology Department (D.A. McDonald, D.A. Marchuk), Duke University Medical Center, Durham, NC; the University of Chicago Medical Center (C.S., R.S., F.L., I.A.A.), Biological Sciences Division, University of Chicago, Chicago, IL; and the Department of Medicine (R.A.S., M.H.G.), University of California, San Diego, San Diego, CA.
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- Robert Shenkar
- From the Molecular Genetics and Microbiology Department (D.A. McDonald, D.A. Marchuk), Duke University Medical Center, Durham, NC; the University of Chicago Medical Center (C.S., R.S., F.L., I.A.A.), Biological Sciences Division, University of Chicago, Chicago, IL; and the Department of Medicine (R.A.S., M.H.G.), University of California, San Diego, San Diego, CA.
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- Rebecca A. Stockton
- From the Molecular Genetics and Microbiology Department (D.A. McDonald, D.A. Marchuk), Duke University Medical Center, Durham, NC; the University of Chicago Medical Center (C.S., R.S., F.L., I.A.A.), Biological Sciences Division, University of Chicago, Chicago, IL; and the Department of Medicine (R.A.S., M.H.G.), University of California, San Diego, San Diego, CA.
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- Feifei Liu
- From the Molecular Genetics and Microbiology Department (D.A. McDonald, D.A. Marchuk), Duke University Medical Center, Durham, NC; the University of Chicago Medical Center (C.S., R.S., F.L., I.A.A.), Biological Sciences Division, University of Chicago, Chicago, IL; and the Department of Medicine (R.A.S., M.H.G.), University of California, San Diego, San Diego, CA.
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- Mark H. Ginsberg
- From the Molecular Genetics and Microbiology Department (D.A. McDonald, D.A. Marchuk), Duke University Medical Center, Durham, NC; the University of Chicago Medical Center (C.S., R.S., F.L., I.A.A.), Biological Sciences Division, University of Chicago, Chicago, IL; and the Department of Medicine (R.A.S., M.H.G.), University of California, San Diego, San Diego, CA.
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- Douglas A. Marchuk
- From the Molecular Genetics and Microbiology Department (D.A. McDonald, D.A. Marchuk), Duke University Medical Center, Durham, NC; the University of Chicago Medical Center (C.S., R.S., F.L., I.A.A.), Biological Sciences Division, University of Chicago, Chicago, IL; and the Department of Medicine (R.A.S., M.H.G.), University of California, San Diego, San Diego, CA.
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- Issam A. Awad
- From the Molecular Genetics and Microbiology Department (D.A. McDonald, D.A. Marchuk), Duke University Medical Center, Durham, NC; the University of Chicago Medical Center (C.S., R.S., F.L., I.A.A.), Biological Sciences Division, University of Chicago, Chicago, IL; and the Department of Medicine (R.A.S., M.H.G.), University of California, San Diego, San Diego, CA.
抄録
<jats:sec> <jats:title>Background and Purpose—</jats:title> <jats:p>Cerebral cavernous malformations (CCMs) are characterized by grossly dilated capillaries, associated with vascular leak and hemorrhage, and occur in sporadic or inherited (autosomal-dominant) forms with mutations in 1 of 3 gene loci (CCM 1, 2 or 3). We previously reported that the CCM1 protein (KRIT1) localizes to endothelial cell–cell junctions and loss of KRIT1 leads to junctional instability associated with activation of RhoA and its effector Rho kinase. Although Rho kinase inhibition has been proposed as potential therapy for CCM, there has been no demonstration of a therapeutic effect on CCM lesion genesis in vivo.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods—</jats:title> <jats:p> Our recently generated a model of CCM1 disease ( <jats:italic>Ccm1</jats:italic> <jats:sup>+/−</jats:sup> <jats:italic>Msh2</jats:italic> <jats:sup>−/−</jats:sup> ) was treated with the Rho kinase inhibitor fasudil (100 mg/kg/day administered in drinking water from weaning to 5 months of age), or placebo, and blindly assessed CCM lesion burden by systematic survey of animals' brains. For comparison, we also assessed therapeutic effect in previously described <jats:italic>Ccm2</jats:italic> <jats:sup>+/−</jats:sup> <jats:italic>Trp53</jats:italic> <jats:sup>−/−</jats:sup> mice treated with the same dose and duration of fasudil and placebo. </jats:p> </jats:sec> <jats:sec> <jats:title>Results—</jats:title> <jats:p> Fasudil-treated <jats:italic>Ccm1</jats:italic> <jats:sup>+/−</jats:sup> <jats:italic>Msh2</jats:italic> <jats:sup>−/−</jats:sup> mice had a significantly decreased prevalence of CCM lesions compared with placebo controls. Lesions in treated animals were smaller and less likely associated with hemorrhage, inflammation, and endothelial proliferation and exhibited decreased expression of Rho kinase activation biomarkers. A therapeutic effect was also documented in <jats:italic>Ccm2</jats:italic> <jats:sup>+/−</jats:sup> <jats:italic>Trp53</jats:italic> <jats:sup>−/−</jats:sup> mice. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions—</jats:title> <jats:p>This represents the first report of therapeutic benefit of pharmacological therapy in development and progression of CCMs and indicates that Rho kinase activation is a critical step in CCM lesion genesis and maturation.</jats:p> </jats:sec>
収録刊行物
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- Stroke
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Stroke 43 (2), 571-574, 2012-02
Ovid Technologies (Wolters Kluwer Health)