Impairments of retinal hemodynamics and oxygen metrics in ocular hypertension-induced ischemia-reperfusion

Rahimi, Masoud; Leahy, Sophie; Matei, Nathanael; Burford, James; Blair, Norman P.; Shahidi, Mahnaz

doi:10.1016/j.exer.2022.109278

Cited by 5 publications

(3 citation statements)

References 38 publications

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“…As we know, elevated IOP in glaucoma is associated with impaired blood flow to the retina and optic nerves, resulting in ischemic and hypoxic damage to the neuroretinal tissue [22,23]. Lowering IOP has proven beneficial in alleviating the mechanical compression and vascular compromise that occur in glaucoma.…”

Section: Discussionmentioning

confidence: 99%

HIF-1α Reduction by Lowering Intraocular Pressure Alleviated Retinal Neovascularization

Yang,

Ni,

Zhou

et al. 2023

Biomolecules

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Hypoxia-induced retinal neovascularization is a leading cause of blindness worldwide. Oxygen-induced retinopathy (OIR) mouse, a well-established angiogenesis model, has been extensively used to evaluate the effect of anti-angiogenic agents through intravitreal injection. Here, we serendipitously found that the needles used for intravitreal injection caused an unexpected “anti-angiogenic” effect in the OIR mice. To evaluate the effects of various intravitreal puncture sizes on retinal neovascularization and explore the potential underlying mechanism, intravitreal punctures using 0.5 mm (25 G), 0.3 mm (30 G), or 0.21 mm (33 G) needles were performed in OIR mice. Compared with 0.3 mm and 0.21 mm puncture, the 0.5 mm puncture remarkably suppressed the formation of pathological angiogenesis, inhibited vascular leakage, and remodeled the retinal vasculature. Mechanistically, the 0.5 mm puncture induced a substantial reduction in intraocular pressure (IOP), leading to an improvement in oxygen partial pressure (pO2) and significant reduction in Hif1a expression, resulting in resolution of angiogenic and inflammatory responses. Furthermore, IOP-lowering drugs, Travatan or Azarga, also promoted the alleviation of hypoxia and exhibited a potent anti-angiogenesis efficacy. Our study revealed an acute and significant reduction in IOP caused by a large puncture, which could remarkably suppress HIF-1α-mediated retinal neovascularization, indicating that lowering IOP may be a promising therapeutic avenue for treating retinal neovascular diseases.

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Section: Discussionmentioning

confidence: 99%

HIF-1α Reduction by Lowering Intraocular Pressure Alleviated Retinal Neovascularization

Yang,

Ni,

Zhou

et al. 2023

Biomolecules

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“…Characterized by irreversible retinal ganglion cells (RGCs) degeneration, retinal ischemia and reperfusion (IR) constitute the pathological mechanisms of various vision-threatening diseases, such as diabetic retinopathy and glaucoma [ 1 , 2 ]. In glaucomatous eyes, increased intraocular pressure (IOP) restricts retinal blood supply and triggers a self-reinforcing destructive cascade to RGCs, which is further exacerbated by subsequent reperfusion [ 3 , 4 ]. However, current treatments targeting retinal IR injury have yielded unsatisfactory results, necessitating the exploration of the pathogenesis and potential treatments from a novel perspective.…”

Section: Introductionmentioning

confidence: 99%

“…See figure on next page.) Fig 4. EMPA ameliorates inflammation through the regulation of mitochondria homeostasis in microglia.…”

mentioning

confidence: 97%

Empagliflozin targets Mfn1 and Opa1 to attenuate microglia-mediated neuroinflammation in retinal ischemia and reperfusion injury

Yang,

Liu,

Chen

et al. 2023

J Neuroinflammation

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Background Neuroinflammation and mitochondrial dysfunction play crucial roles in retinal ischemia and reperfusion (IR) injury. Recent studies have identified mitochondrial function as a promising target for immunomodulation. Empagliflozin (EMPA), an anti-diabetic drug, has exhibited great potential as both an anti-inflammatory agent and a protector of mitochondrial health. This study aimed to assess the therapeutic efficacy of EMPA in retinal IR injury. Methods To evaluate the protective effects of EMPA, the drug was injected into the vitreous body of mice post-retinal IR. Single-cell RNA sequencing (scRNA-seq) analysis was conducted to uncover the underlying mechanisms, and the results were further validated through in vivo and in vitro experiments. Results EMPA effectively protected retinal ganglion cells (RGCs) from IR injury by attenuating local retinal inflammation. The scRNA-seq analysis revealed that EMPA downregulated the nucleotide-binding domain and leucine-rich repeat containing protein 3 (NLRP3) signaling pathway and restored mitochondrial dynamics by upregulating the expression of mitochondrial fusion-related genes, Mitofusin 1 (Mfn1) and optic atrophy 1 (Opa1). These findings were further corroborated by Western blotting. In vitro experiments provided additional insights, demonstrating that EMPA suppressed lipopolysaccharide (LPS)-induced cell inflammation and NLRP3 inflammasome activation. Moreover, EMPA enhanced mitochondrial fusion, neutralized mitochondrial reactive oxygen species (mtROS), and restored mitochondrial membrane potential (MMP) in BV2 microglia. Notably, genetic ablation of Mfn1 or Opa1 abolished the anti-inflammatory effects of EMPA. Conclusions Our findings highlight the positive contribution of Mfn1 and Opa1 to the anti-inflammatory therapeutic effect of EMPA. By restoring mitochondrial dynamics, EMPA effectively mitigates microglia-mediated neuroinflammation and prevents RGC loss in retinal IR injury.

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Natural compounds efficacy in Ophthalmic Diseases: A new twist impacting ferroptosis

Yuan,

He,

Xiang

et al. 2024

Biomedicine & Pharmacotherapy

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Impairments of retinal hemodynamics and oxygen metrics in ocular hypertension-induced ischemia-reperfusion

Cited by 5 publications

References 38 publications

HIF-1α Reduction by Lowering Intraocular Pressure Alleviated Retinal Neovascularization

HIF-1α Reduction by Lowering Intraocular Pressure Alleviated Retinal Neovascularization

Empagliflozin targets Mfn1 and Opa1 to attenuate microglia-mediated neuroinflammation in retinal ischemia and reperfusion injury

Natural compounds efficacy in Ophthalmic Diseases: A new twist impacting ferroptosis

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