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Pin1 inhibitor Juglone prevents diabetic vascular dysfunction


Costantino, Sarah; Paneni, Francesco; Lüscher, Thomas F; Cosentino, Francesco (2016). Pin1 inhibitor Juglone prevents diabetic vascular dysfunction. International Journal of Cardiology, 203:702-707.

Abstract

BACKGROUND: Atherosclerosis is a major cause of mortality in patients with diabetes. However, novel breakthrough therapies have yet to be approved in this setting. Prolyl-isomerase-1 (Pin1) is emerging as a key molecule implicated in vascular oxidative stress and inflammation. In the present study, we investigate whether pharmacological inhibition of Pin1 may protect against diabetes-induced oxidative stress, endothelial dysfunction and vascular inflammation.
METHODS AND RESULTS: Experiments were performed in human aortic endothelial cells (HAECs) exposed to normal (5mmol/L) or high glucose (25mmol/L) concentrations, in the presence of Pin1 inhibitor Juglone (10μM) or vehicle (<1% ethanol). In parallel, streptozotocin-induced diabetic mice were treated with Juglone i.p. every other day for 30days (1mg/Kg). Organ chamber experiments were performed in aortic rings to assess endothelium-dependent relaxations to acetylcholine (Ach 10(-9) to 10(-6)mol/L). Mitochondrial oxidative stress, organelle integrity as well as NF-kB-dependent inflammatory signatures were determined both in HAECs and aortas from diabetic mice. In HAECs, ambient hyperglycemia increased mitochondrial superoxide anion generation while treatment with Juglone prevented this phenomenon. Pharmacological inhibition of Pin1 also preserved mitochondrial integrity, nitric oxide availability and endothelial expression of adhesion molecules. Interestingly enough, endothelial dysfunction, oxidative stress and NF-kB-driven inflammation were significantly attenuated in diabetic mice chronically treated with Juglone as compared to vehicle-treated animals.
CONCLUSION: Pharmacological inhibition of Pin1 by Juglone prevents hyperglycemia-induced vascular dysfunction. Taken together, our findings may set the stage for novel therapeutic approaches to prevent vascular complications in patients with diabetes.

Abstract

BACKGROUND: Atherosclerosis is a major cause of mortality in patients with diabetes. However, novel breakthrough therapies have yet to be approved in this setting. Prolyl-isomerase-1 (Pin1) is emerging as a key molecule implicated in vascular oxidative stress and inflammation. In the present study, we investigate whether pharmacological inhibition of Pin1 may protect against diabetes-induced oxidative stress, endothelial dysfunction and vascular inflammation.
METHODS AND RESULTS: Experiments were performed in human aortic endothelial cells (HAECs) exposed to normal (5mmol/L) or high glucose (25mmol/L) concentrations, in the presence of Pin1 inhibitor Juglone (10μM) or vehicle (<1% ethanol). In parallel, streptozotocin-induced diabetic mice were treated with Juglone i.p. every other day for 30days (1mg/Kg). Organ chamber experiments were performed in aortic rings to assess endothelium-dependent relaxations to acetylcholine (Ach 10(-9) to 10(-6)mol/L). Mitochondrial oxidative stress, organelle integrity as well as NF-kB-dependent inflammatory signatures were determined both in HAECs and aortas from diabetic mice. In HAECs, ambient hyperglycemia increased mitochondrial superoxide anion generation while treatment with Juglone prevented this phenomenon. Pharmacological inhibition of Pin1 also preserved mitochondrial integrity, nitric oxide availability and endothelial expression of adhesion molecules. Interestingly enough, endothelial dysfunction, oxidative stress and NF-kB-driven inflammation were significantly attenuated in diabetic mice chronically treated with Juglone as compared to vehicle-treated animals.
CONCLUSION: Pharmacological inhibition of Pin1 by Juglone prevents hyperglycemia-induced vascular dysfunction. Taken together, our findings may set the stage for novel therapeutic approaches to prevent vascular complications in patients with diabetes.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Cardiology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:15 January 2016
Deposited On:28 Dec 2015 11:00
Last Modified:08 Dec 2017 16:21
Publisher:Elsevier
ISSN:0167-5273
Publisher DOI:https://doi.org/10.1016/j.ijcard.2015.10.221
PubMed ID:26583846

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