Homocysteine: A Potential Biomarker for Diabetic Retinopathy

Tawfik, Amany; Mohamed, Riyaz; Elsherbiny, Nehal M.; DeAngelis, Margaret M.; Bartoli, Manuela; Al‐Shabrawey, Mohamed

doi:10.3390/jcm8010121

Cited by 65 publications

(68 citation statements)

References 55 publications

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“…STA-670, San Diego, CA, USA), according to the protocol provided with the kit. Final absorbance was measured at 450 nm using an ELISA plate reader [28].…”

Section: Homocysteinementioning

confidence: 99%

Faulty homocysteine recycling in diabetic retinopathy

2020

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Background: Although hyperglycemia is the main instigator in the development of diabetic retinopathy, elevated circulating levels of a non-protein amino acid, homocysteine, are also associated with an increased risk of retinopathy. Homocysteine is recycled back to methionine by methylenetetrahydrofolate reductase (MTHFR) and/or transsulfurated by cystathionine β-synthase (CBS) to form cysteine. CBS and other transsulfuration enzyme cystathionine-γ-lyase (CSE), through desulfuration, generates H 2 S. Methionine cycle also regulates DNA methylation, an epigenetic modification associated with the gene suppression. The aim of this study was to investigate homocysteine and its metabolism in diabetic retinopathy. Methods: Homocysteine and H 2 S levels were analyzed in the retina, and CBS, CSE and MTHFR in the retinal microvasculature from human donors with established diabetic retinopathy. Mitochondrial damage was evaluated in retinal microvessels by quantifying enzymes responsible for maintaining mitochondrial dynamics (fission-fusionmitophagy). DNA methylation status of CBS and MTHFR promoters was examined using methylated DNA immunoprecipitation technique. The direct effect of homocysteine on mitochondrial damage was confirmed in human retinal endothelial cells (HRECs) incubated with 100 μM L-homocysteine. Results: Compared to age-matched nondiabetic control human donors, retina from donors with established diabetic retinopathy had~3-fold higher homocysteine levels and~50% lower H 2 S levels. The enzymes important for both transsulfuration and remethylation of homocysteine including CBS, CSE and MTHFR, were 40-60% lower in the retinal microvasculature from diabetic retinopathy donors. While the mitochondrial fission protein, dynamin related protein 1, and mitophagy markers optineurin and microtubule-associated protein 1A/1B-light chain 3 (LC3), were upregulated, the fusion protein mitofusin 2 was downregulated. In the same retinal microvessel preparations from donors with diabetic retinopathy, DNA at the promoters of CBS and MTHFR were hypermethylated. Incubation of HRECs with homocysteine increased reactive oxygen species and decreased transcripts of mtDNA-encoded CYTB. Conclusions: Compromised transsulfuration and remethylation processes play an important role in the poor removal of retinal homocysteine in diabetic patients. Thus, regulation of their homocysteine levels should ameliorate retinal mitochondrial damage, and by regulating DNA methylation status of the enzymes responsible for homocysteine transsulfuration and remethylation, should prevent excess accumulation of homocysteine.

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“…STA-670, San Diego, CA, USA), according to the protocol provided with the kit. Final absorbance was measured at 450 nm using an ELISA plate reader [28].…”

Section: Homocysteinementioning

confidence: 99%

Faulty homocysteine recycling in diabetic retinopathy

2020

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“…In diabetes, while retinal MMP-9 expression is upregulated, that of Timp1 is downregulated [6,7]. Diabetic patients routinely have increased levels of a non-protein amino acid, homocysteine [8], and high plasma homocysteine is correlated with decreased retinal nerve layer thickness and the severity of diabetic retinopathy [9][10][11][12]. Our recent study has shown three-fold higher homocysteine levels in the retina from human donors with established diabetic retinopathy compared to retina from nondiabetic human donors [13].…”

Section: Introductionmentioning

confidence: 93%

Homocysteine Disrupts Balance between MMP-9 and Its Tissue Inhibitor in Diabetic Retinopathy: The Role of DNA Methylation

Mohammad

Kowluru

2020

IJMS

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High homocysteine is routinely observed in diabetic patients, and this non-protein amino acid is considered as an independent risk factor for diabetic retinopathy. Homocysteine biosynthesis from methionine forms S-adenosyl methionine (SAM), which is a major methyl donor critical in DNA methylation. Hyperhomocysteinemia is implicated in increased oxidative stress and activation of MMP-9, and in diabetic retinopathy, the activation of MMP-9 facilitates capillary cell apoptosis. Our aim was to investigate the mechanism by which homocysteine activates MMP-9 in diabetic retinopathy. Human retinal endothelial cells, incubated with/without 100 μM homocysteine, were analyzed for MMP-9 and its tissue inhibitor Timp1 expressions and interactions, and ROS levels. Timp1 and MMP-9 promoters were analyzed for methylated and hydroxymethylated cytosine levels (5mC and 5hmC respectively) by the DNA capture method, and DNA- methylating (Dnmt1) and hydroxymethylating enzymes (Tet2) binding by chromatin immunoprecipitation. The results were confirmed in retinal microvessels from diabetic rats receiving homocysteine. Homocysteine supplementation exacerbated hyperglycaemia-induced MMP-9 and ROS levels and decreased Timp1 and its interactions with MMP-9. Homocysteine also aggravated Dnmts and Tets activation, increased 5mC at Timp1 promoter and 5hmC at MMP-9 promoter, and suppressed Timp1 transcription and activated MMP-9 transcription. Similar results were obtained from retinal microvessels from diabetic rats receiving homocysteine. Thus, hyperhomocysteinemia in diabetes activates MMP-9 functionally by reducing Timp1-MMP-9 interactions and transcriptionally by altering DNA methylation-hydroxymethylation of its promoter. The regulation of homocysteine could prevent/slow down the development of retinopathy and prevent their vision loss in diabetic patients.

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“…Sottilotta et al found that elevated plasma homocysteine could be an independent risk factor of retinal vascular occlusive disease which is closely related to coronary, cerebral, and peripheral atherosclerotic vascular disease [15]. A previous study also the evaluate the availability of HCY as a biomarker for diabetic retinopathy screening, and the result was that HCY could be a strong candidate [4]. Retinopathy described above was closely related to the damage of the retinal vessels.…”

Section: Discussionmentioning

confidence: 98%

“…The patients in this study all suffered from hypertension, and the difference of retinal abnormalities were caused by HCY. However, whether HCY damages retinal vessels through the superposition effect of hypertension or directly damages retinal vessels remains controversial [4,12]. Serum HCY is a sulfur-containing amino acid, which is an important intermediate product produced during the metabolism of methionine and cysteine.…”

Section: Discussionmentioning

confidence: 99%

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The Association Between Retinal Vessel Abnormalities and H-type Hypertension

Huang

Yun

Huang

et al. 2020

Preprint

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Introduction: This study aimed to investigate the relationship between H-type hypertension and retinal vessel abnormalities. Methods: Hypertensive patients were retrospectively enrolled in this study. According to serum homocysteine (HCY), patients were divided into isolated hypertension and H-type hypertension group. Retinal fundus photography was used to evaluate the diameter of retinal vessels and retinopathy. Univariate and multivariate regression were used to investigate difference of retinal vessel abnormalities between H-type hypertension and isolated hypertension patients. Results: A total of 191 hypertensive patients were included, of which 85 were isolated hypertension and 106 were H-type hypertension. H-type hypertension patients had a higher ratio of retinopathy(P=0.004) and higher degree of retinal arteriosclerosis (P=0.005). CRAE(P=0.002) and AVR(P=0.001) were smaller in H-type hypertension group. Multivariate analysis showed that after adjusting for age, sex, course of hypertension and diabetes, H-type hypertension were still risk factor of retinopathy(OR, 2.259; 95%CI, 1.165—4.378; P=0.016), CRAE (B=-5.669; 95%CI, -9.452—-1.886; P=0.004), and AVR(B=-0.023; 95%CI,-0.039—-0.007; P=0.005). Conclusion: H-type hypertension may aggravate retinal vessel abnormalities compared with isolated hypertension.

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Homocysteine: A Potential Biomarker for Diabetic Retinopathy

Cited by 65 publications

References 55 publications

Faulty homocysteine recycling in diabetic retinopathy

Faulty homocysteine recycling in diabetic retinopathy

Homocysteine Disrupts Balance between MMP-9 and Its Tissue Inhibitor in Diabetic Retinopathy: The Role of DNA Methylation

The Association Between Retinal Vessel Abnormalities and H-type Hypertension

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