Inhibition of PKC   by Oral Administration of Ruboxistaurin Is Well Tolerated and Ameliorates Diabetes-Induced Retinal Hemodynamic Abnormalities in Patients

Aiello, Lloyd Paul; Clermont, Allen C.; Arora, Vipin; Davis, Matthew D.; Sheetz, Matthew J.; Bursell, S.E.

doi:10.1167/iovs.05-0757

Cited by 132 publications

(85 citation statements)

References 26 publications

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“…No significant within-or between-group effects of ruboxistaurin were demonstrated for the remaining efficacy measures. TEAEs were similar between groups, and the adverse event profile was consistent with that previously reported for ruboxistaurin (12,(31)(32)(33)(34)(35).…”

Section: Safety Profilesupporting

confidence: 87%

A 6-Month, Randomized, Double-Masked, Placebo-Controlled Study Evaluating the Effects of the Protein Kinase C-β Inhibitor Ruboxistaurin on Skin Microvascular Blood Flow and Other Measures of Diabetic Peripheral Neuropathy

et al. 2007

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OBJECTIVE -Diabetes leads to protein kinase C (PKC)-␤ overactivation and microvascular dysfunction, possibly resulting in disordered skin microvascular blood flow (SkBF) and other changes observed in diabetic peripheral neuropathy (DPN) patients. We investigate the effects of the isoform-selective PKC-␤ inhibitor ruboxistaurin mesylate on neurovascular function and other measures of DPN.RESEARCH DESIGN AND METHODS -Endothelium-dependent and C fibermediated SkBF, sensory symptoms, neurological deficits, nerve fiber morphometry, quantitative sensory and autonomic function testing, nerve conduction studies, quality of life (using the Norfolk Quality-of-Life Questionnaire for Diabetic Neuropathy [QOL-DN]), and adverse events were evaluated for 20 placebo-and 20 ruboxistaurin-treated (32 mg/day) DPN patients (aged Ն18 years; with type 1 or type 2 diabetes and A1C Յ11%) during a randomized, doublemasked, single-site, 6-month study.RESULTS -Endothelium-dependent (ϩ78.2%, P Ͻ 0.03) and C fiber-mediated (ϩ56.4%, P Ͻ 0.03) SkBF at the distal calf increased from baseline to end point. Significant improvements from baseline within the ruboxistaurin group were also observed for the Neuropathy Total Symptom Score-6 (NTSS-6) (3 months Ϫ48.3%, P ϭ 0.01; end point Ϫ66.0%, P Ͻ 0.0006) and the Norfolk QOL-DN symptom subscore and total score (end point Ϫ41.2%, P ϭ 0.01, and Ϫ41.0, P ϭ 0.04, respectively). Between-group differences in baseline-to-end point change were observed for NTSS-6 total score (placebo Ϫ13.1%; ruboxistaurin Ϫ66.0%, P Ͻ 0.03) and the Norfolk QOL-DN symptom subscore (placebo Ϫ4.0%; ruboxistaurin Ϫ41.2%, P ϭ 0.041). No significant ruboxistaurin effects were demonstrated for the remaining efficacy measures. Adverse events were consistent with those observed in previous ruboxistaurin studies.CONCLUSIONS -In this cohort of DPN patients, ruboxistaurin enhanced SkBF at the distal calf, reduced sensory symptoms (NTSS-6), improved measures of Norfolk QOL-DN, and was well tolerated. Diabetes Care 30:896 -902, 2007

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Section: Safety Profilesupporting

confidence: 87%

A 6-Month, Randomized, Double-Masked, Placebo-Controlled Study Evaluating the Effects of the Protein Kinase C-β Inhibitor Ruboxistaurin on Skin Microvascular Blood Flow and Other Measures of Diabetic Peripheral Neuropathy

et al. 2007

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“…The findings reveal a potentially important mechanism of regulation of LXR that warrants further study as abnormal PKC signaling has been observed in diabetes, atherosclerosis, renin expression and glucose metabolism in the liver, all conditions in which LXR is known to play an important role (Collins 2004, Grefhorst et al 2005, Aiello et al 2006, Dey et al 2006.…”

Section: Discussionmentioning

confidence: 91%

Protein kinase C α modulates liver X receptor α transactivation

Delvecchio¹,

Capone²

2008

Journal of Endocrinology

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Liver X receptor a (LXRa), an oxysterol-activated nuclear hormone receptor, regulates the expression of genes involved in lipid and cholesterol homeostasis and inflammation. We show here that transactivation by LXRa in monkey kidney COS-1 (Cos-1) cells is decreased by activation of the protein kinase C (PKC) signaling pathway. In transient co-transfection assays, phorbol myristate acetate (PMA) suppressed LXR-dependent transactivation of LXR-responsive reporter genes or the natural promoter of the human ATP-binding cassette (ABC), ABCA1 gene. The decrease in LXR transactivation after PMA treatment was also observed in human embryonic kidney (HEK) 293 and human hepatocellular carcinoma (HepG2) cells. Moreover, endogenous LXR target genes, ABCA1 and sterol response element-binding protein-1c, were also decreased by PMA treatment in HEK293 cells as assessed by real-time PCR. The PMA-mediated decrease of LXR activity was blocked by the PKC inhibitor bisindolylmaleimide and mimicked by constitutively active PKCa. Nuclear extracts treated with PMA show no decrease in LXRa DNA binding as assessed by mobility shift and chromatin immunoprecipitation assays. Additionally, in vitro kinase assays demonstrate that PKCa can phosphorylate LXRa. Our findings reveal a mode of regulation of LXRa that may be relevant to disease conditions where aberrant PKC signaling is observed, such as diabetes.

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“…9,10 Naturally, attenuation of PKC-b activity has been coupled to amelioration of HG-induced retinal and glomerular microvascular complications to which inhibitions of ZO-1 and occludin translocation and the small GTPase RhoA post-translational modification appear to contribute. [11][12][13] It is noteworthy in this context that the increased presence of PKC-b protein has also been documented in the brain infarcts of deceased ischemic stroke patients. 14 Guanosine triphosphate-binding proteins, in particular RhoA, have crucial roles in many cellular processes, including the regulation of endothelial barrier integrity and function.…”

Section: Introductionmentioning

confidence: 85%

PKC-βExacerbatesin vitroBrain Barrier Damage in Hyperglycemic Settings via Regulation of RhoA/Rho-kinase/MLC2 Pathway

Srivastava

Shao

Bayraktutan

2013

J Cereb Blood Flow Metab

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Stroke patients with hyperglycemia (HG) develop higher volumes of brain edema emerging from disruption of blood-brain barrier (BBB). This study explored whether inductions of protein kinase C-b (PKC-b) and RhoA/Rho-kinase/myosin-regulatory light chain-2 (MLC2) pathway may account for HG-induced barrier damage using an in vitro model of human BBB comprising human brain microvascular endothelial cells (HBMEC) and astrocytes. Hyperglycemia (25 mmol/L D-glucose) markedly increased RhoA/Rho-kinase protein expressions (in-cell westerns), MLC2 phosphorylation (immunoblotting), and PKC-b (PepTag assay) and RhoA (Rhotekinbinding assay) activities in HBMEC while concurrently reducing the expression of tight junction protein occludin. Hyperglycemiaevoked in vitro barrier dysfunction, confirmed by decreases in transendothelial electrical resistance and concomitant increases in paracellular flux of Evan's blue-labeled albumin, was accompanied by malformations of actin cytoskeleton and tight junctions. Suppression of RhoA and Rho-kinase activities by anti-RhoA immunoglobulin G (IgG) electroporation and Y-27632, respectively prevented morphologic changes and restored plasma membrane localization of occludin. Normalization of glucose levels and silencing PKC-b activity neutralized the effects of HG on occludin and RhoA/Rho-kinase/MLC2 expression, localization, and activity and consequently improved in vitro barrier integrity and function. These results suggest that HG-induced exacerbation of the BBB breakdown after an ischemic stroke is mediated in large part by activation of PKC-b.

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Inhibition of PKC by Oral Administration of Ruboxistaurin Is Well Tolerated and Ameliorates Diabetes-Induced Retinal Hemodynamic Abnormalities in Patients

Cited by 132 publications

References 26 publications

A 6-Month, Randomized, Double-Masked, Placebo-Controlled Study Evaluating the Effects of the Protein Kinase C-β Inhibitor Ruboxistaurin on Skin Microvascular Blood Flow and Other Measures of Diabetic Peripheral Neuropathy

A 6-Month, Randomized, Double-Masked, Placebo-Controlled Study Evaluating the Effects of the Protein Kinase C-β Inhibitor Ruboxistaurin on Skin Microvascular Blood Flow and Other Measures of Diabetic Peripheral Neuropathy

Protein kinase C α modulates liver X receptor α transactivation

PKC-βExacerbatesin vitroBrain Barrier Damage in Hyperglycemic Settings via Regulation of RhoA/Rho-kinase/MLC2 Pathway

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