Relaxation of porcine retinal arterioles exposed to hypercholesterolemia in vivo is modified by hepatic LDL-receptor deficiency and diabetes mellitus

Bek, Toke; Al-Mashhadi, Rozh H; Misfeldt, Mikkel; Riis-Vestergaard, Mette Ji; Bentzon, Jacob F.; Pedersen, Simon Metz Mariendal

doi:10.1016/j.exer.2013.06.013

Cited by 8 publications

(3 citation statements)

References 29 publications

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“…The pig model (including transgenics) has also been used for studying autoregulatory function in the retinal vasculature using electrophysiological approaches(Hansen et al, 2015; Misfeldt et al, 2010a, b). In the context of diabetic retinopathy, Bek et al examined retinal vessels from diabetic pigs over-expressing the gain-of-function mutant (D374Y) of the human gene PCSK9 that blocks LDL transport and demonstrated that in the presence of both hyperglycemia and dyslipidemia there was a marked reduction in vasogenic tone regulation and structure of retinal arterioles(Bek et al, 2013a).Non-human primates provide the ultimate model of clinical diabetic retinopathy since these animals are anatomically closest to humans and their retina has a true macula. There have been several research teams examining retinopathy following T1D in rhesus monkeys.…”

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confidence: 98%

The progress in understanding and treatment of diabetic retinopathy

Stitt

Curtis

Chen

et al. 2016

Progress in Retinal and Eye Research

875

657

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mentioning

confidence: 98%

The progress in understanding and treatment of diabetic retinopathy

Stitt

Curtis

Chen

et al. 2016

Progress in Retinal and Eye Research

875

657

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“…So far, there are not any data in the literature studying the involvement of PCSK9 in the development of AMD. One experimental study used minipigs overexpressing a gain-of-function mutant (D374Y) of the human gene PCSK9 with a consequent experimental hypercholesterolemia and found advanced atheromatosis of retinal arterioles caused by lipid overload [36]. The nding of increased plasma PCSK9 in the AMD patients predispose them to the long-lasting hypercholesterolemia and related atherogenic changes in the retinal arteries.…”

Section: Discussionmentioning

confidence: 99%

The Impact of Rheohaemapheresis on the Proprotein Convertase Subtilisin Kexin 9 (PCSK9) in Age-Related Macular Degeneration

Bláha

Langrová

Bláha

et al. 2020

Preprint

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Background. Age-related macular degeneration (AMD) is a progressive chronic disease with resulting visual impairment or even blindness with limited therapeutic options. Because hyperlipidemia is a significant risk factor for AMD development we investigated long-term effects of rheohaemapheresis in the dry form of age-related macular degeneration on the lipid related parameters including PCSK9.Methods. This study evaluates 31 patients with age-related macular degeneration (AMD), treated with rheohaemapheresis. The followed-up period was 7 years. Average age was 69.1 ± 4.9 years. Each treated patient received a series of 8 sessions of rheohaemapheresis. 2 additional procedures within 1-week procedures were performed to boost the effect after the 2-year period. We measured the drusenoid pigment epithelium detachment (DPED), best-corrected visual acuity (BCVA), electroretinography (ERG), lipid, inflammatory, endothelial dysfunction and rheologically important parameters. Results. Rheohaemapheresis treatment in AMD patients was associated with a significant decrease of total cholesterol, LDL-C, HDL-C, apoprotein B, and lipoprotein (a) levels, biomarkers of inflammation, endothelial dysfunction (CD40L, MCP-1) and rheologically important parameters, and serum PCSK9 (P<0.001). The patients were further divided into 2 groups based on the ophtalmological examination. Successfully treated patients (n=10, with at least a 5-year follow-up) had significantly lower baseline LDL-C and ApoB (P<0.05) and their serum PCSK9 significantly decreased after rheohaemapheresis (P<0.001) in comparison to the patients where treatment failured (n=4). Conclusion. Over the long term, rheohaemapheresis reduced the DPED, improved the function of photoreceptors, and prevented the decline of BCVA. BCVA improvement was accompanied by lowering of LDL-C and PCSK9 and improvement of endothelial dysfunction. We suggest that rheohaemapheresis and other novel anti-PCSK9 therapies may be used synergistically to reduce severity, slow down or even induce regression of AMD.

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“…Thus, it has been shown that ATP stimulates intracellular calcium activity in perivascular cells [34,35], and intracellular calcium levels are elevated in retinal cell cultures exposed to hyperglycaemia [8]. Furthermore, retinal blood flow is affected by activation of P 2 receptors in alloxan-induced diabetes in rabbits [36,37], and a recent study has shown that ATP relaxation of porcine retinal arterioles exposed to hypercholesterolaemia in vivo is modified by both hepatic low-density lipoprotein receptor deficiency and diabetes mellitus [38]. …”

Section: Discussionmentioning

confidence: 99%

Purinergic Mechanisms and Prostaglandin E Receptors Involved in ATP-Induced Relaxation of Porcine Retinal Arterioles in vitro

Riis-Vestergaard

Bek²

2015

Ophthalmic Res

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Purpose: Adenosine triphosphate (ATP) is involved in the tone regulation of retinal arterioles, and the effect may be direct, through ATP degradation or mediated by cyclo-oxygenase products. However, the relative contribution of these mechanisms and the extent to which the mechanisms are active in the retinal vascular wall or depend on the perivascular retinal tissue are unknown. Methods: Porcine retinal arterioles with perivascular retinal tissue were mounted in a wire myograph for isometric tone recordings. The relaxing effects of ATP and the non-degradable analogue ATP-γS were studied in the presence of antagonists to ATP, adenosine and prostaglandin E (EP) receptors. The experiments were repeated after removal of the perivascular retinal tissue. Results: ATP induced a significant concentration-dependent relaxation of retinal arterioles (p < 0.05) which was reduced after removal of perivascular retinal tissue. The effect was due to non-degraded ATP and a degradation product of ATP acting via adenosine receptors. Relaxation was reduced by ibuprofen and blocking of EP₁ receptors. Conclusion: ATP-induced relaxation of retinal arterioles is mediated by ATP, ATP degradation products and by stimulation of EP₁ receptors, involving both the perivascular retina and the vascular wall. The findings emphasize the complexity of purinergic effects in the regulation of retinal vascular tone.

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Relaxation of porcine retinal arterioles exposed to hypercholesterolemia in vivo is modified by hepatic LDL-receptor deficiency and diabetes mellitus

Cited by 8 publications

References 29 publications

The progress in understanding and treatment of diabetic retinopathy

The progress in understanding and treatment of diabetic retinopathy

The Impact of Rheohaemapheresis on the Proprotein Convertase Subtilisin Kexin 9 (PCSK9) in Age-Related Macular Degeneration

Purinergic Mechanisms and Prostaglandin E Receptors Involved in ATP-Induced Relaxation of Porcine Retinal Arterioles in vitro

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