A novel imidazolinone metformin‐methylglyoxal metabolite promotes endothelial cell angiogenesis via the eNOS/HIF‐1α pathway

Nguyen, Huong Thanh; Koh, Jia Yi; Li, Hainan; Islas-Robles, Argel; Venkata, Sai Pranathi Meda; Wang, Jiemei; Monks, Terrence J.

doi:10.1096/fj.202002674rr

Cited by 6 publications

(7 citation statements)

References 55 publications

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“…Human Proangiogenic Protein Array. ECs at 80% confluence were transfected with Ad-GPR39 or Ad-GFP as control, and the Proteome Profiler Human Angiogenesis Array (R&D Systems, #ARY007) was performed as described previously (58).…”

Section: Methodsmentioning

confidence: 99%

“…pnas.org saphenous vein were ligated while the animal was under anesthesia (58). Blood flow was measured before, immediately after, and at 1, 7, 11, 14, 21, and 28 d after femoral arterial ligation using laser Doppler imaging and a PeriScan PIM 3 System (Perimed).…”

Section: Methodsmentioning

confidence: 99%

“…Immunofluorescent Staining. Muscle samples from hind limb ischemia studies were collected and embedded in OCT. Immunofluorescent staining was performed as previously described (58). Fluorescence images were recorded by fluorescence microscopy (EVOS; Thermo Fisher Scientific).…”

Section: Methodsmentioning

confidence: 99%

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Inhibition of GPR39 restores defects in endothelial cell–mediated neovascularization under the duress of chronic hyperglycemia: Evidence for regulatory roles of the sonic hedgehog signaling axis

Venkata

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Impaired endothelial cell (EC)–mediated angiogenesis contributes to critical limb ischemia in diabetic patients. The sonic hedgehog (SHH) pathway participates in angiogenesis but is repressed in hyperglycemia by obscure mechanisms. We investigated the orphan G protein–coupled receptor GPR39 on SHH pathway activation in ECs and ischemia-induced angiogenesis in animals with chronic hyperglycemia. Human aortic ECs from healthy and type 2 diabetic (T2D) donors were cultured in vitro. GPR39 mRNA expression was significantly elevated in T2D. The EC proliferation, migration, and tube formation were attenuated by adenovirus-mediated GPR39 overexpression (Ad-GPR39) or GPR39 agonist TC-G-1008 in vitro. The production of proangiogenic factors was reduced by Ad-GPR39. Conversely, human ECs transfected with GPR39 siRNA or the mouse aortic ECs isolated from GPR39 global knockout (GPR39 KO ) mice displayed enhanced migration and proliferation compared with their respective controls. GPR39 suppressed the basal and ligand-dependent activation of the SHH effector GLI1, leading to attenuated EC migration. Coimmunoprecipitation revealed that the GPR39 direct binding of the suppressor of fused (SUFU), the SHH pathway endogenous inhibitor, may achieve this. Furthermore, in ECs with GPR39 knockdown, the robust GLI1 activation and EC migration were abolished by SUFU overexpression. In a chronic diabetic model of diet-induced obesity (DIO) and low-dose streptozotocin (STZ)-induced hyperglycemia, the GPR39 KO mice demonstrated a faster pace of revascularization from hind limb ischemia and lower incidence of tissue necrosis than GPR39 wild-type (GPR39 WT ) counterparts. These findings have provided a conceptual framework for developing therapeutic tools that ablate or inhibit GPR39 for ischemic tissue repair under metabolic stress.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Inhibition of GPR39 restores defects in endothelial cell–mediated neovascularization under the duress of chronic hyperglycemia: Evidence for regulatory roles of the sonic hedgehog signaling axis

Venkata

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…Metformin, the first-line drug for type 2 diabetic mellitus, also has a specific regulatory effect on the process of angiogenesis. The research found that intraperitoneal injection of metformin exhibits potential for improving endothelial function and the wound-healing process in mice models without affecting their blood glucose levels 188 . Recent studies have also revealed that another FDA-approved anti-diabetic class of drugs, gliflozins, which lower blood glucose by suppressing kidney glucose reabsorption by inhibiting sodium-glucose cotransporter 2 (SGLT2) 189 , are also potential small molecule drug candidate for treating PAD.…”

Section: Trends In Therapeutic Angiogenesis For Padmentioning

confidence: 99%

Therapeutic angiogenesis-based strategy for peripheral artery disease

Han¹,

Luo²,

Marcelina³

et al. 2022

Theranostics

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Peripheral artery disease (PAD) poses a great challenge to society, with a growing prevalence in the upcoming years. Patients in the severe stages of PAD are prone to amputation and death, leading to poor quality of life and a great socioeconomic burden. Furthermore, PAD is one of the major complications of diabetic patients, who have higher risk to develop critical limb ischemia, the most severe manifestation of PAD, and thus have a poor prognosis. Hence, there is an urgent need to develop an effective therapeutic strategy to treat this disease. Therapeutic angiogenesis has raised concerns for more than two decades as a potential strategy for treating PAD, especially in patients without option for surgery-based therapies. Since the discovery of gene-based therapy for therapeutic angiogenesis, several approaches have been developed, including cell-, protein-, and small molecule drug-based therapeutic strategies, some of which have progressed into the clinical trial phase. Despite its promising potential, efforts are still needed to improve the efficacy of this strategy, reduce its cost, and promote its worldwide application. In this review, we highlight the current progress of therapeutic angiogenesis and the issues that need to be overcome prior to its clinical application.

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“…In addition, endothelial nitric oxide synthase (eNOS) produces nitric oxide to help regulate vascular function and participates in the regulation of EC repair and proliferation 14 . Our previous study suggested that eNOS exerts biological functions downstream of miR-126-5p; however, its expression level is positively correlated with that of miR-126-5p 10 .…”

Section: Introductionmentioning

confidence: 99%

Delta-like factor 1 negatively regulates angiogenesis as a target gene of miR-126-5p after indirect revascularization surgery in patients with moyamoya disease

et al. 2022

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Promoting endothelial cell (EC) proliferation and angiogenesis after indirect revascularization surgery is crucial for decreasing the stroke rate in moyamoya patients. However, the role of delta-like factor 1 (DLK1) in regulating EC proliferation in chronically ischaemic brains and the specific mechanisms remain unclear. Therefore, we compared the expression levels of DLK1 in the dura mater (DM) tissues of patients with moyamoya disease and patients with aneurysms, and dual luciferase reporter and RNA binding protein immunoprecipitation assays were conducted to determine whether DLK1 is a target gene of miR-126-5p. The effect of DLK1 on EC proliferation and the interaction between DLK1 and miR-126-5p were explored in vitro. Then, we established an animal model of two-vessel occlusion together with encephalo-myo-synangiosis (2VO+EMS). The temporalis muscles (TMs) of the animals were transfected with DLK1 lentiviral RNA (Lv-DLK1) and short hairpin RNA (sh-DLK1) to compare the DLK1 expression, angiogenesis (CD31 count), and numbers of vacuoles and impaired tight junctions in the ECs of TM-covered chronically ischaemic brains as well as the cognitive improvement in each group. DLK1 expression was lower in the DM tissues of moyamoya patients than in those of the aneurysm patients, and DLK1 was identified as a target gene of miR-126-5p. In vitro, DLK1 inhibited EC proliferation, migration and angiogenesis and exerted effects opposite those of miR-126-5p. In 2VO+EMS rats, compared to the control transfection, the TM transfection of Lv-DLK1 induced significantly higher DLK1 expression and worse angiogenesis in the TM-covered ischaemic brain as well as less extensive cognitive improvement, while the transfection of sh-DLK1 into the TM had the opposite effects. In summary, DLK1, a target gene of miR-126-5p, negatively regulates angiogenesis in chronically ischaemic brains and is expected to be a new target to improve the efficacy of indirect revascularization surgery and the prognosis of moyamoya patients.

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A novel imidazolinone metformin‐methylglyoxal metabolite promotes endothelial cell angiogenesis via the eNOS/HIF‐1α pathway

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 6 publications

References 55 publications

Inhibition of GPR39 restores defects in endothelial cell–mediated neovascularization under the duress of chronic hyperglycemia: Evidence for regulatory roles of the sonic hedgehog signaling axis

Inhibition of GPR39 restores defects in endothelial cell–mediated neovascularization under the duress of chronic hyperglycemia: Evidence for regulatory roles of the sonic hedgehog signaling axis

Therapeutic angiogenesis-based strategy for peripheral artery disease

Delta-like factor 1 negatively regulates angiogenesis as a target gene of miR-126-5p after indirect revascularization surgery in patients with moyamoya disease

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