Dual endothelin receptor antagonism with bosentan reverses established vascular remodeling and dysfunctional angiogenesis in diabetic rats: Relevance to glycemic control

Abdelsaid, Mohammed; Kaczmarek, Jessica; Coucha, Maha; Ergul, Adviye

doi:10.1016/j.lfs.2014.01.008

Cited by 35 publications

(35 citation statements)

References 20 publications

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“…Given that DPP-4 inhibitors display pleiotropic effects independent of glycemic control (13, 14) and our previous study showed that inhibition of the ET system by bosentan also prevented and reversed dysfunctional cerebral angiogenesis in the GK model of diabetes (17), we next investigated the direct effects and interaction of linagliptin with ET-1 on proangiogenic properties of primary BMVECs isolated from control or diabetic animals. As we previously reported (16), BMVECs from diabetic GK rats have erratic migratory properties that resemble the chaotic vascularization seen in vivo and our current data show that linagliptin decreases tube formation and migration in these cells.…”

Section: Discussionmentioning

confidence: 99%

Linagliptin attenuates diabetes-induced cerebral pathological neovascularization in a blood glucose-independent manner: Potential role of ET-1

et al. 2016

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Aims We have shown that glycemic control with metformin or endothelin-1 (ET-1) inhibition with bosentan prevents and restores diabetes-mediated cerebral pathological remodeling and neovascularization. Our recent data suggest that linagliptin, a member of the dipeptidyl peptidase-4 inhibitor class of glucose-lowering agents, prevents cerebrovascular remodeling and dysfunction independent of its blood glucose lowering effects. We hypothesized that linagliptin prevents pathological neovascularization via the modulation of the ET-1 system. Materials and Methods 24-week old diabetic Goto-Kakizaki and nondiabetic Wistar rats were treated for 4 weeks with either vehicle chow or chow containing 166mg/kg linagliptin. At termination, FITC-dextran was injected to visualize the vasculature. Brain sections were imaged by confocal microscopy for vascular density, tortuosity, vascular volume, and surface in both the cortex and striatum. Retinal acellular capillary formation was measured. Brain microvascular endothelial cells (BMVEC) isolated from control or diabetic rats were treated with linagliptin with or without ET-1 dual receptor antagonist and tested for angiogenic properties with cell migration and tube formation assays. Key Finding Linagliptin reduced all indices of cerebral neovascularization compared with control rats. In vitro, linagliptin normalized the augmented angiogenic properties of BMVECs isolated from diabetic animals and bosentan reversed this response. Cells from diabetic animals had higher ET-1 and less ETB receptors than in control cells. Linagliptin significantly decreased ET-1 levels and increased ETB receptors. Significance ET system contributes to pathological neovascularization in diabetes as evidenced by restoration of functional angiogenesis by bosentan treatment and prevention of linagliptin-mediated improvement of angiogenesis in the in vitro model.

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Section: Discussionmentioning

confidence: 99%

Linagliptin attenuates diabetes-induced cerebral pathological neovascularization in a blood glucose-independent manner: Potential role of ET-1

et al. 2016

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“…For instance, bosentan alleviates increased neovascularization and leaky vessels in cerebrovascular system of a type 2-diabetic animal model and inhibits tumor vascularization and bone metastasis in an animal model of breast carcinoma cell metastasis [106,107]. This is also the case in SSc because the number of nailfold ramified capillaries, which reflect activated angiogenesis, is decreased after a one-year administration of bosentan [108].…”

Section: Bosentanmentioning

confidence: 95%

Vasculopathy in scleroderma

2015

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Systemic sclerosis (SSc) is a multisystem connective tissue disorder featured by vascular injury and fibrosis of the skin and various internal organs with autoimmune background. Although the pathogenesis of SSc still remains elusive, it is generally accepted that initial vascular injury due to autoimmunity and/or environmental factors causes structural and functional abnormalities of vasculature which eventually result in the constitutive activation of fibroblasts in various organs. Structural alterations consist of destructive vasculopathy (loss of small vessels) and proliferative obliterative vasculopathy (occlusion of arterioles and small arteries with fibro-proliferative change) caused by impaired compensatory vasculogenesis and angiogenesis. Impaired function of SSc vasculature includes the altered expression of cell adhesion molecules predominantly inducing Th2 and Th17 cell infiltration, endothelial dysfunction primarily due to the low availability of nitric oxide, the activated endothelial-to-mesenchymal transition leading to fibro-proliferative vascular change and tissue fibrosis, and the impaired coagulation/fibrinolysis system promoting the formation of intravascular fibrin deposits. Recent new insights into the therapeutic mechanisms of intravenous cyclophosphamide pulse and bosentan and the establishment of a new SSc animal model (Klf5 (+/-);Fli1 (+/-) mice) provide us useful clues to further understand the development of vascular alterations characteristic of SSc. This article overviewed the present understanding of the pathogenesis of SSc vasculopathy.

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“…Elevation of ET-1 has been well documented in patients and experimental models in diabetes (Matsumoto et al, 2004; Takahashi et al, 1990). Dual endothelin receptor blockade prevents cerebrovascular dysfunction and improper neovascularization as well as improvement in hippocampal-based cognitive tasks in diabetes (Abdelsaid et al, 2014a, 2014b; Singh et al, 2014). Overexpression of endothelial ET-1 impairs BBB function and worsens cognitive dysfunction after ischemic injury (Zhang et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Relationship of endothelin-1 and NLRP3 inflammasome activation in HT22 hippocampal cells in diabetes

Ward

Ergul

2016

Life Sciences

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Diabetes increases the risk and worsens the progression of cognitive decline. Diabetic rats treated with the dual endothelin receptor antagonist bosentan, have been shown to improve hippocampal-based cognitive deficits. The NLRP3 inflammasome has been implicated in vascular complications of diabetes. We hypothesized that diabetes-mediated increase in endothelin-1 (ET-1) in hippocampal cells causes NLRP3 activation and inflammation. An in vitro model was employed by exposing HT22 hippocampal cells to normal (25 mM), low (5.5 mM) and high (50 mM) glucose conditions with and without palmitate (200 μM) in the presence and absence of 10 μM bosentan for 24 hours. NLRP3 activity was measured by western blotting for cryopyrin and caspase-1. ET-1 and IL-1β expression was determined by ELISA. HT22 cells synthesize high levels of ET-1 in normal conditions, which was reduced with palmitate and bosentan as well as low and high glucose conditions. Decreased ET-1 levels were associated with greater activation of NLRP3 and IL-1β in normal glucose. High glucose increased NLRP3 markers and activation compared to normal and low glucose. These data suggest that ET-1 may be protective to neurons. Although endothelin antagonism may be beneficial in improving vascular dysfunction and cognitive impairment, its impact on hippocampal neurons should be further explored.

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Dual endothelin receptor antagonism with bosentan reverses established vascular remodeling and dysfunctional angiogenesis in diabetic rats: Relevance to glycemic control

Cited by 35 publications

References 20 publications

Linagliptin attenuates diabetes-induced cerebral pathological neovascularization in a blood glucose-independent manner: Potential role of ET-1

Linagliptin attenuates diabetes-induced cerebral pathological neovascularization in a blood glucose-independent manner: Potential role of ET-1

Vasculopathy in scleroderma

Relationship of endothelin-1 and NLRP3 inflammasome activation in HT22 hippocampal cells in diabetes

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