Heme Synthesis Inhibition Blocks Angiogenesis via Mitochondrial Dysfunction

Shetty, Trupti; Sishtla, Kamakshi; Park, Bomina; Repass, Matthew J.; Corson, Timothy W.

doi:10.1016/j.isci.2020.101391

Cited by 23 publications

(34 citation statements)

References 56 publications

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“…Fech inhibition using chemical inhibitor NMPP led to mitochondrial dysfunction in murine retina by decreasing oxidative phosphorylation, ATP production, and reduced cytochrome c oxidase expression. 11 We further sought to characterize mitochondrial bioenergetics of retinal tissue from Fech m1Pas mice and establish a baseline OCR of oxidative phosphorylation ( Fig. 6 A).…”

Section: Resultsmentioning

confidence: 99%

“…For retinal ex vivo oxygen consumption rate (OCR) measurements, protocols were adapted as previously described. 11 , 21 , 22 Briefly, eyes were enucleated and the retina was isolated from the posterior cup. Retinal punches (1 mm diameter) were dissected from an area adjacent to the optic nerve to minimize variability in retinal thickness.…”

Section: Methodsmentioning

confidence: 99%

“…We have previously described how FECH and thus heme are involved in ocular neovascularization. 9 – 11 We showed that Fech m1Pas mice, both homozygotes and heterozygotes, had reduced lesions in the laser-induced choroidal neovascularization (L-CNV) model. 9 In the oxygen-induced retinopathy (OIR) model, again heterozygous and homozygous Fech m1Pas mice showed a significant reduction in retinal neovascularization and vaso-obliteration compared to age-matched WT animals, with markedly diminished vascular cell proliferation in the retina.…”

mentioning

confidence: 99%

“…However, it was overexpressed in and around neovascular lesions in the L-CNV and OIR models, as well as in eyes from human patients with wet age-related macular degeneration. 9 – 11 …”

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confidence: 99%

“…Acute inhibition of Fech in vivo using a chemical analog of PPIX, N -methyl protoporphyrin (NMPP), 12 markedly decreased mitochondrial bioenergetics of the retina and caused a selective dysfunction in cytochrome c oxidase of the electron transport chain. 11 …”

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confidence: 99%

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Retinal Phenotyping of Ferrochelatase Mutant Mice Reveals Protoporphyrin Accumulation and Reduced Neovascular Response

Pasha

Shetty

Lambert-Cheatham

et al. 2021

Invest. Ophthalmol. Vis. Sci.

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Purpose Heme depletion, through inhibition of ferrochelatase (FECH), blocks retinal and choroidal neovascularization. Both pharmacologic FECH inhibition and a partial loss-of-function Fech mutation ( Fech m1Pas ) are associated with decreased neovascularization. However, the ocular physiology of Fech m1Pas mice under basal conditions has not been characterized. Here, we aimed to characterize the retinal phenotype of Fech m1Pas mice. Methods We monitored retinal vasculature at postnatal day 17, 2 months, and 6 months in Fech m1Pas homozygotes, heterozygotes, and their wild-type littermates. We characterized Fech substrate protoporphyrin (PPIX) fluorescence in the eye (excitation = 403 nm, emission = 628 nm), retinal function by electroretinogram, visual acuity by optomotor reflex, and retinal morphology by optical coherence tomography and histology. We stained vasculature using isolectin B4 and fluorescein angiography. We determined endothelial sprouting of retinal and choroidal tissue ex vivo and bioenergetics of retinal punches using a Seahorse flux analyzer. Results Fundi, retinal vasculature, venous width, and arterial tortuosity showed no aberrations. However, VEGF-induced retinal and choroidal sprouting was decreased in Fech m1Pas mutants. Homozygous Fech m1Pas mice had pronounced buildup of PPIX in the posterior eye with no damage to visual function, bioenergetics, and integrity of retinal layers. Conclusions Even with a buildup of PPIX in the retinal vessels in Fech m1Pas homozygotes, the vasculature remains normal. Notably, stimulus-induced ex vivo angiogenesis was decreased in Fech m1Pas mutants, consistent with reduced pathologic angiogenesis seen previously in neovascular animal models. Our findings indicate that Fech m1Pas mice are a useful model for studying the effects of heme deficiency on neovascularization due to Fech blockade.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

“…However, it was overexpressed in and around neovascular lesions in the L-CNV and OIR models, as well as in eyes from human patients with wet age-related macular degeneration. 9 – 11 …”

mentioning

confidence: 99%

mentioning

confidence: 99%

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Retinal Phenotyping of Ferrochelatase Mutant Mice Reveals Protoporphyrin Accumulation and Reduced Neovascular Response

Pasha

Shetty

Lambert-Cheatham

et al. 2021

Invest. Ophthalmol. Vis. Sci.

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Angiogenic activity of mitochondria; beyond the sole bioenergetic organelle

Sadeghsoltani,

Hassanpour,

Safari

et al. 2024

Journal Cellular Physiology

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Angiogenesis is a complex process that involves the expansion of the pre‐existing vascular plexus to enhance oxygen and nutrient delivery and is stimulated by various factors, including hypoxia. Since the process of angiogenesis requires a lot of energy, mitochondria play an important role in regulating and promoting this phenomenon. Besides their roles as an oxidative metabolism base, mitochondria are potential bioenergetics organelles to maintain cellular homeostasis via sensing alteration in oxygen levels. Under hypoxic conditions, mitochondria can regulate angiogenesis through different factors. It has been indicated that unidirectional and bidirectional exchange of mitochondria or their related byproducts between the cells is orchestrated via different intercellular mechanisms such as tunneling nanotubes, extracellular vesicles, and gap junctions to maintain the cell homeostasis. Even though, the transfer of mitochondria is one possible mechanism by which cells can promote and regulate the process of angiogenesis under reperfusion/ischemia injury. Despite the existence of a close relationship between mitochondrial donation and angiogenic response in different cell types, the precise molecular mechanisms associated with this phenomenon remain unclear. Here, we aimed to highlight the possible role of mitochondria concerning angiogenesis, especially the role of mitochondrial transport and the possible relation of this transfer with autophagy, the housekeeping phenomenon of cells, and angiogenesis.

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Long‐Acting Microparticle Formulation of Griseofulvin for Ocular Neovascularization Therapy

Chobisa,

Muniyandi,

Sishtla

et al. 2023

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Neovascular age‐related macular degeneration (nAMD) is a leading cause of vision loss in older adults. nAMD is treated with biologics targeting vascular endothelial growth factor; however, many patients do not respond to the current therapy. Here, a small molecule drug, griseofulvin (GRF), is used due to its inhibitory effect on ferrochelatase, an enzyme important for choroidal neovascularization (CNV). For local and sustained delivery to the eyes, GRF is encapsulated in microparticles based on poly(lactide‐co‐glycolide) (PLGA), a biodegradable polymer with a track record in long‐acting formulations. The GRF‐loaded PLGA microparticles (GRF MPs) are designed for intravitreal application, considering constraints in size, drug loading content, and drug release kinetics. Magnesium hydroxide is co‐encapsulated to enable sustained GRF release over >30 days in phosphate‐buffered saline with Tween 80. Incubated in cell culture medium over 30 days, the GRF MPs and the released drug show antiangiogenic effects in retinal endothelial cells. A single intravitreal injection of MPs containing 0.18 µg GRF releases the drug over 6 weeks in vivo to inhibit the progression of laser‐induced CNV in mice with no abnormality in the fundus and retina. Intravitreally administered GRF MPs prove effective in preventing CNV, providing proof‐of‐concept toward a novel, cost‐effective nAMD therapy.

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Heme Synthesis Inhibition Blocks Angiogenesis via Mitochondrial Dysfunction

Cited by 23 publications

References 56 publications

Retinal Phenotyping of Ferrochelatase Mutant Mice Reveals Protoporphyrin Accumulation and Reduced Neovascular Response

Retinal Phenotyping of Ferrochelatase Mutant Mice Reveals Protoporphyrin Accumulation and Reduced Neovascular Response

Angiogenic activity of mitochondria; beyond the sole bioenergetic organelle

Long‐Acting Microparticle Formulation of Griseofulvin for Ocular Neovascularization Therapy

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