Mechanistic insights into glucose induced vascular epigenetic reprogramming in type 2 diabetes

Dhawan, Priyal; Vasishta, Sampara; Balakrishnan, Aswath; Joshi, Manjunath B.

doi:10.1016/j.lfs.2022.120490

Cited by 15 publications

(15 citation statements)

References 175 publications

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“…Finally, the DR mouse model was induced; Cx43 knockdown was achieved through lentivirus infection to evaluate the in-vivo effects of Cx43 knockdown on DR angiogenesis. During diabetic retinopathy, high glucose causes endothelial cells to undergo a bidirectional activation of the inflammatory and epigenetic machinery, which eventually results in chronic inflammation and vascular problems, causing globally high morbidity and mortality (27,28). Therefore, our findings identify Cx43siRNA as a druggable target for DR via regulating endothelial angiogenesis.…”

Section: Introductionmentioning

confidence: 78%

Connexin 43 (Cx43) regulates high-glucose-induced retinal endothelial cell angiogenesis and retinal neovascularization

2022

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Diabetic retinopathy (DR) is an important microvascular complication of type 1 and type 2 diabetes mellitus (DM) and a major cause of blindness. Retinal neovascularization plays a critical role in the proliferative DR. In this study, high glucose-induced connexin 43 (Cx43) expression in human retinal endothelial cells (hRECs) in a dose-dependent manner. Compared with hRECs under normal culture conditions, high-glucose (HG)-stimulated hRECs showed promoted tubule formation, increased ROS release, and elevated levels of tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), vascular endothelial growth factor A (VEGFA), and intercellular adhesion molecule 1 (ICAM-1) in the culture medium. HG-induced alterations were further magnified after Cx43 overexpression, whereas partially eliminated after Cx43 knockdown. Finally, in the DR mouse model, impaired retinal structure, increased CD31 expression, and elevated mRNA levels of TNF-α, IL-1β, VEGFA, and ICAM-1 were observed; in-vivo Cx43 knockdown partially reversed these phenomena. Conclusively, Cx43 knockdown could inhibit hREC angiogenesis, therefore improving DR in the mouse model.

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Section: Introductionmentioning

confidence: 78%

Connexin 43 (Cx43) regulates high-glucose-induced retinal endothelial cell angiogenesis and retinal neovascularization

2022

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“…Contrarily, we found that HbA1c was improved by training. Since HbA1c is related to better glucose metabolism, which indicates greater redox balance, one can expect a better vascular system [ 58 ]. Next, the evaluation of vascular condition should be multi-dimensional.…”

Section: Discussionmentioning

confidence: 99%

Does Aerobic plus Machine-Assisted Resistance Training Improve Vascular Function in Type 2 Diabetes? A Systematic Review and Meta-Analysis of Randomized Controlled Trials with Trial Sequential Analysis

Guo

Zhang³

et al. 2022

JCM

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Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by hyperglycemia, insulin resistance, and pancreatic B cell dysfunction. Hyperglycemia can cause several complications, including nephrological, neurological, ophthalmological, and vascular complications. Many modalities, such as medication, physical therapies, and exercise, are developed against vascular disorders. Among all exercise forms, aerobic plus machine-assisted resistance training is widely applied. However, whether this intervention can significantly improve vascular conditions remains controversial. In this study, an electronic search was processed for the Pubmed, Embase, and Cochrane libraries for randomized controlled trials (RCTs) comparing the efficacy of aerobic plus machine-assisted resistance training with no exercise (control) on patients with T2DM. Pulse wave velocity (PWV), the index of arterial stiffness, was chosen as primary outcome. The reliability of the pooled outcome was tested by trial sequential analysis (TSA). Secondary outcomes included systolic blood pressure (SBP) and hemoglobin A1c (HbA1c). Finally, five RCTs with a total of 328 patients were included. Compared with control, aerobic plus machine-assisted resistance training failed to provide significant improvement on PWV (MD −0.54 m/s, 95% CI [−1.69, 0.60], p = 0.35). On the other hand, TSA indicated that this results till needs more verifications. Additionally, this training protocol did not significantly decrease SBP (MD −1.05 mmHg, 95% CI [−3.71, 1.61], p = 0.44), but significantly reduced the level of HbA1c (MD −0.55%, 95% CI [−0.88, −0.22], p = 0.001). In conclusion, this meta-analysis failed to detect a direct benefit of aerobic plus machine-assisted resistance training on vascular condition in T2DM population. Yet the improvement in HbA1c implied a potential of this training method in mitigating vascular damage. More studies are needed to verify the benefit.

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“…N 6 -methyladenosine (m 6 A), the most common RNA chemical modi cation on posttranscription, could participate in numerous pathophysiological processes (Dhawan, et al, 2022, Ye, et al, 2022. In the vasculopathy, more and more literatures have indicated the essential roles of m 6 A.…”

Section: Discussionmentioning

confidence: 99%

N6-methyladenosine (m 6 A) IGF2BP1 regulates high glucose-induced vascular endothelial cells apoptosis via targeting HMGB1

Liang

Liu²,

Wei

et al. 2022

Preprint

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In diabetes mellitus pathophysiology, high glucose (HG)-induced vascular endothelial dysfunction is associated with the progress of diabetes vascular complications. Besides, N6-methyladenosine (m6A) has been reported to participate in the vascular biological characteristic. Nevertheless, the underlying mechanisms of high glucose (HG)-related m6A regulation on vascular endothelial cells are still not entirely clear. The proliferation and apoptosis was detected using EdU assay and flow cytometry. The m6A modified level was identified by m6A quantification analysis and MeRIP-PCR. The molecular interaction within IGF2BP1 and HMGB1 was determined by RIP-PCR. Results indicated that m6A reader insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) up-regulated in HG-administrated Human umbilical vascular endothelium cells (HUVECs) as compared to normal glucose group. Functionally, results indicated that IGF2BP1 knockdown recovered the proliferation of HUVECs inhibited by HG-administration. Besides, IGF2BP1 knockdown reduced the apoptosis triggered by HG-administration. Mechanistically, IGF2BP1 interacts with HMGB1 mRNA and stabilized its expression of m6A-modified RNA. Therefore, these findings provide compelling evidence demonstrating that m6A reader IGF2BP1 contributes to the proliferation and apoptosis of vascular endothelial cells in hyperglycaemia, serving as a target for the development of diabetic angiopathy therapeutics.

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Mechanistic insights into glucose induced vascular epigenetic reprogramming in type 2 diabetes

Cited by 15 publications

References 175 publications

Connexin 43 (Cx43) regulates high-glucose-induced retinal endothelial cell angiogenesis and retinal neovascularization

Connexin 43 (Cx43) regulates high-glucose-induced retinal endothelial cell angiogenesis and retinal neovascularization

Does Aerobic plus Machine-Assisted Resistance Training Improve Vascular Function in Type 2 Diabetes? A Systematic Review and Meta-Analysis of Randomized Controlled Trials with Trial Sequential Analysis

N6-methyladenosine (m 6 A) IGF2BP1 regulates high glucose-induced vascular endothelial cells apoptosis via targeting HMGB1

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