β2–Adrenergic Receptor Antagonism Attenuates CNV Through Inhibition of VEGF and IL-6 Expression

Lavine, Jeremy A.; Farnoodian, Mitra; Wang, Shoujian; Darjatmoko, Soesiawati R.; Wright, Lynda S.; Gamm, David M.; Ip, Michael S.; Sorenson, Christine M.

doi:10.1167/iovs.16-20204

Cited by 33 publications

(36 citation statements)

References 46 publications

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“…VEGF, a specific mitogen for endothelial cells, has been identified as a key mediator in the retina and CNV [4]. A number of studies have observed that retinal pigment epithelial (RPE) cell-derived VEGF plays a key role in the progression of CNV [5-7]. VEGF is also increased in the vitreous and CNV membranes of patients with AMD [6, 8].…”

Section: Introductionmentioning

confidence: 99%

Celecoxib Down-Regulates the Hypoxia-Induced Expression of HIF-1α and VEGF Through the PI3K/AKT Pathway in Retinal Pigment Epithelial Cells

Sun¹,

Cai²,

Liu³

2017

Cell Physiol Biochem

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Background/Aims: The goal of this study was to detect the expression of hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) in human retinal pigmented epithelial (RPE) cells treated with celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, under hypoxic and normoxic conditions and to explore the signaling mechanism involved in regulating the hypoxia-induced expression of HIF-1α and VEGF in RPE cells. Methods: D407 cells were cultured in normoxic or hypoxic conditions, with or without celecoxib or a PI3K inhibitor (LY294002). The anti-proliferative effect of celecoxib was assessed using the MTT assay. RT-PCR, Western blotting and ELISA were performed to detect the levels of PI3K, phosphorylated AKT (p-AKT), HIF-1α, VEGF and COX-2. Results: Celecoxib inhibited the proliferation of RPE cells in a dose-dependent manner. Celecoxib suppressed the expression of VEGF at both the mRNA and protein levels and decreased HIF-1α protein expression. HIF-1α activation was regulated by the PI3K/AKT pathway. The celecoxib-induced down-regulation of HIF-1α and VEGF required the suppression of the hypoxia-induced PI3K/AKT pathway. However, the down-regulation of COX-2 did not occur in cells treated with celecoxib. Conclusions: The antiangiogenic effects of celecoxib in RPE cells under hypoxic conditions resulted from the inhibition of HIF-1α and VEGF expression, which may be partly mediated by a COX-2-independent, PI3K/AKT-dependent pathway.

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Section: Introductionmentioning

confidence: 99%

Celecoxib Down-Regulates the Hypoxia-Induced Expression of HIF-1α and VEGF Through the PI3K/AKT Pathway in Retinal Pigment Epithelial Cells

Sun¹,

Cai²,

Liu³

2017

Cell Physiol Biochem

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“…14 The present work demonstrates, for the first time, the modulatory effect of propranolol on the angiogenic activity of MPs in a choroidal explant model; suppression of PEDF action was sufficient to abrogate antineovascular effects of propranolol in choroidal explant. These findings uncover an additional element of complementarity related to actions of propranolol in CNV by acting not only on RPE, choroidal pericytes, and endothelium, 9 but also on invading MPs.…”

Section: Discussionmentioning

confidence: 79%

“…1A-C), consistent with previous reports. 9 The effect of propranolol was associated with reduced IL-6 and TNF expression ( Fig. 1E), both of which promote cell proliferation, [28][29][30] respectively, through the MAPK cascade 31,32 and through augmentation of VEGF transcription.…”

Section: Propranolol Limits Cnv While Increasing Infiltration Of Inflmentioning

confidence: 99%

“…These findings indicate that actions of propranolol on MPs depend on antagonism of more than one or two b-adrenoceptors, in contrast to other cell types. [8][9][10] To elucidate the antiangiogenic properties of propranolol via MPs, we measured inflammatory factors from incubated macrophages J774 cells, which were found to exert the most robust CNV reduction after 24 hours treatment with propranolol (10 lM; compared with other macrophages). Because the effects of propranolol were associated with caspase 3 activation (cleaved caspase 3) on endothelial cells (Fig.…”

Section: Propranolol Restricts Inflammation and Angiogenesis Through mentioning

confidence: 99%

“…More recently, the antiangiogenic properties of propranolol have been demonstrated in a model of CNV. [8][9][10] Although these studies pointed to an effect of propranolol in reducing VEGF, others have questioned this mechanism to fully explain the effects of propranolol, 11,12 while proposing concomitant respective activation of prodeath and suppression of prosurvival factors 5,13 in b-adrenoceptor-bearing vascular cells, 7 suggesting that antiangiogenic mechanisms for propranolol may differ depending on the type of environment and tissue/cell incurring vasoproliferation. In this context, CNV as observed in various clinical conditions as well as in the laser-induced photocoagulation model, is associated with an inflammatory component.…”

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confidence: 99%

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Propranolol Attenuates Proangiogenic Activity of Mononuclear Phagocytes: Implication in Choroidal Neovascularization

Omri

Tahiri

Pierre

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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Targeting b-adrenergic receptor signaling with propranolol has emerged as a potential candidate to counteract choroidal neovascularization (CNV). Little is known of its effect on macrophages, which play a critical role in CNV. We investigated the effect of propranolol on angiogenic response of mononuclear phagocytes (MPs). METHODS. The angiogenic effect of propranolol was evaluated in laser-induced CNV model. Mice received intraperitoneal injections of propranolol (6 mg/kg/d) or vehicle. CNV area and inflammatory cells were determined respectively by using lectin staining and an anti-IBA-1 antibody on RPE/choroid flat mounts. Inflammatory gene expression was evaluated by quantitative (q) PCR analysis. Mechanisms of propranolol was studied in MP cell lines J774 and RAW264.7 and in primary peritoneal macrophages. Expression of pro-and antiangiogenic mediators was studied. In addition, effects of propranolol treatment of MPs was assessed on choroidal explant. RESULTS. CNV was attenuated by propranolol and concomitantly associated with decreased inflammatory mediators IL-6 and TNFa, albeit with accumulation of (b-adrenoceptor harboring) MPs in the CNV area. Conditioned media from MPs preincubated with propranolol exerted antiangiogenic effects. Treatment of J774 confirmed the attenuation of inflammatory response to propranolol and increased cleaved caspase-3 on choroidal explant. We found that propranolol increased pigment epithelium-derived factor (PEDF) expression in MPs. Trapping of PEDF with an antibody abrogated antiangiogenic effects of propranolol. PEDF was also detected in CNV-associated MPs. CONCLUSIONS. We hereby show that propranolol confers on MPs antiangiogenic properties by increasing PEDF expression, which complements its effects on vascular tissue resulting in inhibition of choroidal vasoproliferation in inflammatory conditions. The study supports possible use of propranolol as a therapeutic modality for CNV.

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A Randomized Controlled Pilot Study: Combined 595‐nm Pulsed Dye Laser Treatment and Oxymetazoline Hydrochloride Topical Cream Superior to Oxymetazoline Hydrochloride Cream for Erythematotelangiectatic Rosacea

2021

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Background and Objectives We evaluated if oxymetazoline therapy combined with 595‐nm pulsed dye laser (PDL) will be more beneficial than topical oxymetazoline alone for the improvement of erythematotelangiectatic rosacea. Study Design/Materials and Methods This was a randomized, controlled, prospective clinical trial approved by an independent Institutional Review Board, which enrolled 34 patients with moderate to severe clinical erythema (CEA) into a two‐arm study of PDL with concomitant oxymetazoline cream (Arm 1) and oxymetazoline cream alone (Arm 2). Patients in Arm 1 were treated with 3 monthly laser sessions, which were started after 1 month of topical oxymetazoline cream. Thirty subjects continued with the study, and 25 subjects (Arm 1: 14, Arm 2: 11) completed the 6‐month follow‐up. With photographic comparison to baseline images, efficacy endpoints were based on clinical on‐site grading by both the investigator and the patient, using the grading tools for CEA, Global Aesthetic Improvement (GAI) assessment, vessel size improvement, and subject self‐assessment. These scales were assessed at baseline and/or at each clinical follow‐up at 1, 2, 3, and 6 months. Subject satisfaction as well as post‐treatment immediate response and treatment‐associated pain scores were also evaluated. Results Statistically significant improvement in CEA was seen in both arms at the 1‐, 2‐, and 3‐month post‐baseline visits (P < 0.01). Only Arm 1 presented statistically significant improvement in CEA (P < 0.001) at 6 months post baseline with a mean score of 1.6 (almost clear‐mild) compared with 3.2 at baseline. Arm 1 showed significantly greater mean vessel size improvement at 3 months (P < 0.01) and 6 months (P < 0.05) post baseline compared to Arm 2. Significantly greater improvement (P < 0.05) in the investigator GAI score was reported at the 2‐ and 6‐month follow‐ups compared with Arm 2. Subject GAI scores showed statistically significant greater improvement in Arm 1 compared with Arm 2 at both the 3‐ and 6‐month follow‐ups (P < 0.01). There were no complications or long‐term effects associated with PDL or topical oxymetazoline treatments. Conclusion The prospective trial verifies a safe, enhanced clinical outcome with the combination of PDL therapy and topical oxymetazoline for the treatment of erythematotelangiectatic rosacea patients. Lasers Surg. Med. © 2021 The Authors. Lasers in Surgery and Medicine published by Wiley Periodicals LLC.

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β2–Adrenergic Receptor Antagonism Attenuates CNV Through Inhibition of VEGF and IL-6 Expression

Cited by 33 publications

References 46 publications

Celecoxib Down-Regulates the Hypoxia-Induced Expression of HIF-1α and VEGF Through the PI3K/AKT Pathway in Retinal Pigment Epithelial Cells

Celecoxib Down-Regulates the Hypoxia-Induced Expression of HIF-1α and VEGF Through the PI3K/AKT Pathway in Retinal Pigment Epithelial Cells

Propranolol Attenuates Proangiogenic Activity of Mononuclear Phagocytes: Implication in Choroidal Neovascularization

A Randomized Controlled Pilot Study: Combined 595‐nm Pulsed Dye Laser Treatment and Oxymetazoline Hydrochloride Topical Cream Superior to Oxymetazoline Hydrochloride Cream for Erythematotelangiectatic Rosacea

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