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2014

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Potential of polyphenol-rich natural products to prevent diabetes-induced senescence of endothelial cells

Research unit

UMR 7213 - Laboratoire de biophotonique et pharmacologie
Faculté de Pharmacie, 74 route du Rhin, BP 60024, 67401 ILLKIRCH-GRAFFENSTADEN

Group

Name: Pharmacologie et Physiopathologie cardiovasculaires

Group leader: SCHINI-KERTH Valérie - valerie.schini-kerth@unistra.fr

Group leader's phone: 0368854127

Group organization:
- Chercheurs: 6
- ITA: 3
- Doctorants: 8
- Post-Docs: 2
- Autres: 0

Publications of the team linked to the topic (3 last years):
1) Kim JH, Auger C, Kurita I, Anselm E, Rivoarilala LO, Lee HJ, Lee KW, Schini-Kerth VB. Aronia melanocarpa juice, a rich source of polyphenols, induces endothelium-dependent relaxations in porcine coronary arteries via the redox-sensitive activation of endothelial nitric oxide synthase. Nitric Oxide. 2013; 30;35:54-64.
2) Lee JO, Auger C, Park DH, Kang M, Oak MH, Kim KR, Schini-Kerth VB. An ethanolic extract of Lindera obtusiloba stems, YJP-14, improves endothelial dysfunction, metabolic parameters and physical performance in diabetic db/db mice. PLoS One. 2013; 3;8(6):e65227.
3) Idris Khodja N, Chataigneau T, Auger C, Schini-Kerth VB. Grape-derived polyphenols improve aging-related endothelial dysfunction in rat mesenteric artery: role of oxidative stress and the angiotensin system. PLoS One. 2012;7(2):e32039.

About PhD

PhD Director: AUGER Cyril - cyril.auger@unistra.fr

Phone: 0368854245

Junior advisor: non

Co-tutely: non

Co-Director: non

About PhD topic :

Title: Potential of polyphenol-rich natural products to prevent diabetes-induced senescence of endothelial cells

Project: The cardiovascular complications are the leading cause of death in patients with type 2 diabetes. Indeed, a recent multicenter study indicated that 55 % of diabetic patients died of a cardiovascular disease, with the 50 year-old diabetic patients dying about 6 years younger than non-diabetic subjects. Type 2 diabetes and its micro- and macro-vascular complications are also associated with a premature endothelial dysfunction characterized by a reduction of the endothelium-dependent vasodilatation and appearance of endothelium-derived contractile responses. Indeed, reduced endothelium-dependent relaxation has been reported in arteries isolated from experimental models of type 2 diabetes (db/db mice, OLETF and diabetic fatty Zucker rats).
Recent studies suggest that the induction of an endothelial senescence could contribute to the initiation and development of the endothelial dysfunction. Several inducers of endothelial senescence have been identified including oxidative stress, angiotensin II, hyperglycemia, and advanced glycation end-products. Recently published studies have demonstrated the presence of endothelial senescence in human coronary arteries with atherosclerosis and arteries from diabetic Zucker fatty rats. Moreover, an endothelial dysfunction is induced in rat aorta by the over-expression of the senescence mediator p53 activating a signaling cascade leading to p21-mediated blockade of the cell cycle.
Due to the epidemiological data on the ageing of the population and the recently identified markers of the endothelial senescence, we hypothesize that the hyperglycemia-induced vascular senescence and its associated modifications could play a major role in the impairment of the endothelial function in type 2 diabetic patients.

The present research project aims to determine if natural products rich in vasoprotective polyphenols could delay the endothelial senescence due to the oxidative stress induced by elevated glucose concentration. The project is built on 3 axis:
-       The characterization of the mechanisms involved in the endothelial senescence induced by elevated glucose concentration
Elevated glucose concentration in culture medium of primary culture of endothelial cells isolated from porcine coronary artery will allow the development a cellular model of endothelial senescence induced by hyperglycemia. In addition, we will characterize the molecular and cellular mechanisms involved in the initiation and development of the senescence of endothelial cells in response to cellular stress (role of oxidative stress, p53, p21, eNOS).
-       Evaluation of natural products rich in polyphenols to delay endothelial senescence in vitro
Products rich in polyphenols are known for exerting potent beneficial effects on the endothelial function. The potential of natural products, as well as some polyphenolic molecules composing them, will be evaluated in the cellular model of endothelial senescence in response to glucose. The effects of the products on the molecular and cellular mechanisms identified in the previous step will also be characterized.
-       In vivo evaluation of the beneficial effects of natural products in an experimental model of type 2 diabetes
The most interesting natural products and molecules identified in the in vitro tests will be used for in vivo evaluation using an experimental model of type 2 diabetes such as the diabetic fatty db/db mouse. The involvement in vivo of the mechanisms characterized previously in vitro will also be studied.
This comparative approach aims to identify the mechanisms of the diabetes-induced vascular senescence in order to develop innovative therapeutic targets for vascular protection.

Wished skills: Experience with in vivo experimental models and knowledge of basic cell culture techniques.

Expertises which will be acquired during the training: Cell culture
Vascular reactivity
Western blot
Immunohistochemistry
Confocal microscopy
RT-PCR
Cell cycle analysis
siRNA
in vivo investigations
Scientific communication (publications, posters, oral communications)