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      Rho Kinase Inhibition by Fasudil Ameliorates Diabetes-Induced Microvascular Damage

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          Abstract

          OBJECTIVE—Leukocyte adhesion in retinal microvasuculature substantially contributes to diabetic retinopathy. Involvement of the Rho/Rho kinase (ROCK) pathway in diabetic microvasculopathy and therapeutic potential of fasudil, a selective ROCK inhibitor, are investigated.

          RESEARCH DESIGN AND METHODS—Localization of RhoA/ROCK and Rho activity were examined in retinal tissues of rats. Impact of intravitreal fasudil administration on retinal endothelial nitric oxide synthase (eNOS) and myosin phosphatase target protein (MYPT)-1 phosphorylation, intercellular adhesion molecule-1 (ICAM-1) expression, leukocyte adhesion, and endothelial damage in rat eyes were investigated. Adhesion of neutrophils from diabetic retinopathy patients or nondiabetic control subjects to cultured microvascular endothelial cells was quantified. The potential of fasudil for endothelial protection was investigated by measuring the number of adherent neutrophils and terminal transferase-mediated dUTP nick-end labeling–positive endothelial cells.

          RESULTS—RhoA and ROCK colocalized predominantly in retinal microvessels. Significant Rho activation was observed in retinas of diabetic rats. Intravitreal fasudil significantly increased eNOS phosphorylation, whereas it reduced MYPT-1 phosphorylation, ICAM-1 expression, leukocyte adhesion, and the number of damaged endothelium in retinas of diabetic rats. Neutrophils from diabetic retinopathy patients showed significantly higher adhesion to cultured endothelium and caused endothelial apoptosis, which was significantly reduced by fasudil. Blockade of the Fas-FasL interaction prevented endothelial apoptosis. The protective effect of fasudil on endothelial apoptosis was significantly reversed by Nω-nitro- l-arginine methyl ester, a NOS inhibitor, whereas neutrophil adhesion remained unaffected.

          CONCLUSIONS—The Rho/ROCK pathway plays a critical role in diabetic retinal microvasculopathy. Fasudil protects the vascular endothelium by inhibiting neutrophil adhesion and reducing neutrophil-induced endothelial injury. ROCK inhibition may become a new strategy in the management of diabetic retinopathy, especially in its early stages.

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          Most cited references 45

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          Diabetes

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            A relativistic jetted outburst from a massive black hole fed by a tidally disrupted star

            While gas accretion onto some massive black holes (MBHs) at the centers of galaxies actively powers luminous emission, the vast majority of MBHs are considered dormant. Occasionally, a star passing too near a MBH is torn apart by gravitational forces, leading to a bright panchromatic tidal disruption flare (TDF). While the high-energy transient Swift J164449.3+573451 ("Sw 1644+57") initially displayed none of the theoretically anticipated (nor previously observed) TDF characteristics, we show that the observations (Levan et al. 2011) suggest a sudden accretion event onto a central MBH of mass ~10^6-10^7 solar masses. We find evidence for a mildly relativistic outflow, jet collimation, and a spectrum characterized by synchrotron and inverse Compton processes; this leads to a natural analogy of Sw 1644+57 with a smaller-scale blazar. The phenomenologically novel Sw 1644+57 thus connects the study of TDFs and active galaxies, opening a new vista on disk-jet interactions in BHs and magnetic field generation and transport in accretion systems.
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              CIRCULATION

               SS Chugh (1964)
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                Author and article information

                Journal
                Diabetes
                diabetes
                Diabetes
                American Diabetes Association
                0012-1797
                1939-327X
                January 2009
                : 58
                : 1
                : 215-226
                Affiliations
                [1 ]Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
                [2 ]Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts
                [3 ]Department of Cardiology, Graduate School of Medicine, Tohoku University, Sendai, Japan
                Author notes

                Corresponding author: Yasuaki Hata, hatachan@ 123456med.kyushu-u.ac.jp

                Article
                581215
                10.2337/db08-0762
                2606876
                18840783
                088538fe-ca21-46a9-a602-205a22e26f17
                Copyright © 2009, American Diabetes Association

                Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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                Categories
                Complications

                Endocrinology & Diabetes

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