Simvastatin Inhibits Leukocyte Accumulation and Vascular Permeability in the Retinas of Rats with Streptozotocin-Induced Diabetes

Miyahara, Shinya; Kiryu, Junichi; Yamashiro, Kenji; Miyamoto, Kazuaki; Hirose, Fuyuki; Tamura, Hiroshi; Katsuta, Hideto; Nishijima, Kazuaki; Tsujikawa, Akitaka; Honda, Yoshio

doi:10.1016/s0002-9440(10)63728-5

Cited by 93 publications

(77 citation statements)

References 51 publications

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“…Our investigations of the impact of fasudil on diabetic leukocyte adhesion showed, in line with previous reports, elevated retinal ICAM-1 (34,37) and increased CD18/ CD11b expression on peripheral blood neutrophils (7) of the diabetic animals. These findings indicate higher adhesive properties of both neutrophils and the vascular endothelium during diabetes.…”

Section: Discussionsupporting

confidence: 92%

“…Leukocyte adhesion to retinal vasculature. Retinal vessels and adhering leukocytes in control and diabetic animals were labeled with FITC-conjugated concanavalin A lectin (ConA; Vector Laboratories, Burlingame, CA), as previously described (4,34). Briefly, rats were perfused with 50 ml PBS for 5-10 min to remove intravascular content, including erythrocytes and nonadherent leukocytes.…”

Section: Methodsmentioning

confidence: 99%

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Rho Kinase Inhibition by Fasudil Ameliorates Diabetes-Induced Microvascular Damage

et al. 2009

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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 ofRhoA/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 N-nitro-L-arginine methyl ester, a NOS inhibitor, whereas neutrophil adhesion remained unaffected. CONCLUSIONS-The

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Section: Discussionsupporting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Rho Kinase Inhibition by Fasudil Ameliorates Diabetes-Induced Microvascular Damage

et al. 2009

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“…Although the results of the two drugs were in parallel, the neuro and vascular protective effects of atorvastatin were usually superior to those of FeTPPs, but did not reach significance, a fact possibly attributable to the pleiotropic effects of statins, including antioxidant effects and inhibition of GTP-binding proteins, in addition to their known cholesterol-lowering ability [13,17,[45][46][47][48]. While previous studies examined the protective effects of statins in retinas from ischaemia/reperfusion models or in other tissue from diabetic animals, our study is the first to demonstrate the neuroprotective effects of atorvastatin in the diabetic retina.…”

Section: Discussionmentioning

confidence: 99%

Diabetes-induced peroxynitrite impairs the balance of pro-nerve growth factor and nerve growth factor, and causes neurovascular injury

Al‐Gayyar²,

et al. 2010

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Aims/hypothesis Diabetic retinopathy, the leading cause of blindness in working-age Americans, is characterised by reduced neurotrophic support and increased proinflammatory cytokines, resulting in neurotoxicity and vascular permeability. We sought to elucidate how oxidative stress impairs homeostasis of nerve growth factor (NGF) and its precursor, proform of NGF (proNGF), to cause neurovascular dysfunction in the eye of diabetic patients. Methods Levels of NGF and proNGF were examined in samples from human patients, from retinal Müller glial cell line culture cells and from streptozotocin-induced diabetic animals treated with and without atorvastatin (10 mg/kg daily, per os) or 5,10,15,20-tetrakis (4-sulfonatophenyl) porphyrinato iron (III) chloride (FeTPPs) (15 mg/kg daily, i.p.) for 4 weeks. Neuronal death and vascular permeability were assessed by TUNEL and extravasation of BSA-fluorescein. Results Diabetes-induced peroxynitrite formation impaired production and activity of matrix metalloproteinase-7 (MMP-7), which cleaves proNGF extracellularly, leading to accumulation of proNGF and reducing NGF in samples from diabetic retinopathy patients and experimental models. Treatment of diabetic animals with atorvastatin exerted similar protective effects that blocked peroxynitrite using FeTPPs, restoring activity of MMP-7 and hence the balance between proNGF and NGF. These effects were associated with preservation of blood-retinal barrier integrity, preventing neuronal cell death and blocking activation of RhoA and p38 mitogen-activated protein kinase (p38MAPK) in experimental and human samples. Conclusions/interpretation Oxidative stress plays an unrecognised role in causing accumulation of proNGF, which can activate a common pathway, RhoA/p38MAPK, to mediate neurovascular injury. Oral statin therapy shows promise for treatment of diabetic retinopathy.

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“…Indeed, statins have been shown to decrease permeability of proteins and fluids and thereby decrease the progression of diabetic retinopathy and macular edema (17,18). In addition, a recently published study has shown that simvastatin attenuates leukocyte-endothelial cell interactions and subsequent BRB breakdown (19).…”

Section: Discussionmentioning

confidence: 99%

Statins Ameliorate Endothelial Barrier Permeability Changes in the Cerebral Tissue of Streptozotocin-Induced Diabetic Rats

et al. 2005

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Statins may have favorable effects on endothelial barrier function. The effect of rosuvastatin and simvastatin therapy (10 mg/kg) for 5 weeks on blood-brain barrier (BBB), blood-retinal barrier (BRB), and cardiac muscle permeability of streptozotocin-induced diabetic rats was studied. The size-selective permeability of different vascular beds to a group of fluorescein isothiocyanate dextrans of varying molecular weights was measured. The volume of distribution of 250-, 70-, and 40-kDa dextrans in the cerebral tissue of diabetic rats were significantly increased. The volume of distribution of these dextrans in cerebral tissue was normalized by both statins. Diabetes did not significantly alter the BRB, but both statins decreased the volume of distribution of 70-and 40-kDa dextrans in the retina. The volume of distribution of 40 kDa in cardiac muscle was increased in diabetes, and this change was prevented with statin treatment. Treatment with rosuvastatin and mevalonate (150 mg/kg in drinking water for 5 weeks) did not alter the volume of distribution measurements. We concluded that 1) diabetes in rats is associated with significant changes in the BBB permeability; 2) statin treatment improves the endothelial barrier function in cerebral tissue, retina, and cardiac muscle; and 3) this statin effect could not be attributed to HMGCoA reductase inhibition. Diabetes 54: [2977][2978][2979][2980][2981][2982] 2005 O ne of the sentinel features of atherosclerosis is endothelial cell dysfunction that manifests itself in a variety of ways including poor nitric oxide production, poor vasodilatory response, and increased adhesiveness to leukocytes (1). Another potential endothelial dysfunction commonly observed in diabetes is altered permeability to macromolecules.Diabetes in humans and in animal models has been found to cause significant alterations in endothelial permeability in various vascular beds (2-5). Potential mechanisms underlying the diabetes-related changes in the blood-brain barrier (BBB) include altered expression of key structural and enzymatic proteins, alterations in the lipid composition and fluidity of the membranes, alterations in the neurotransmitter activity, and increased oxidative damage of the endothelial cells (2,6). Another likely contributor to these changes is the activation of protein kinase C that is shown to play an important role in increased permeability of the peripheral and cerebral circulation (7,8). Finally, recent studies have shown that inactivation of the rho-GTPase has a critical role in endothelial barrier function (9,10).Statins are known to have many pleiotropic effects (11). However, the effect of statins on the functional integrity of the microvasculature of diabetic animals has not been well studied. Statins are known to alter endothelial cell function, smooth muscle cell migration and proliferation, and some aspects of vascular inflammation (11). In addition, statins have been shown to improve endothelial barrier permeability in the aorta of Watanabe hyperlipidimic rabbits ...

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Simvastatin Inhibits Leukocyte Accumulation and Vascular Permeability in the Retinas of Rats with Streptozotocin-Induced Diabetes

Cited by 93 publications

References 51 publications

Rho Kinase Inhibition by Fasudil Ameliorates Diabetes-Induced Microvascular Damage

Rho Kinase Inhibition by Fasudil Ameliorates Diabetes-Induced Microvascular Damage

Diabetes-induced peroxynitrite impairs the balance of pro-nerve growth factor and nerve growth factor, and causes neurovascular injury

Statins Ameliorate Endothelial Barrier Permeability Changes in the Cerebral Tissue of Streptozotocin-Induced Diabetic Rats

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