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31 March 2017 : Original article  

Senescence of Pancreas in Middle-Aged Rats with Normal Vascular Function

Mohamad Kassem1ABCDEF*, Zahid Rasul Niazi2B, Malak Abbas2B, Ali El Habhab1C, Guillaume Kreutter1D, Sonia Khemais-Benkhiat2A, Cyril Auger2ABCD, Maria-Cristina Antal3AD, Valérie B. Schini-Kerth2ADE, Florence Toti2ABCDE, Laurence Kessler14ACDEF

DOI: 10.12659/AOT.901009

Ann Transplant 2017; 22:177-186

Abstract

BACKGROUND: In organ transplantation, particularly pancreas transplantation, donor age is a determinant factor for graft survival. Physiological aging is crucial in the progressive deterioration of organs in adulthood. We compared the senescence and function features of pancreas and vascular tissues in young rats and middle-aged rats.

MATERIAL AND METHODS: Islet morphology and the area of cells secreting insulin or glucagon was investigated using immunohistology in young rats (12 weeks) and middle-aged rats (52 weeks) (n=8). Senescence markers, oxidative stress (ROS), and tissue factor (TF) were measured in the rat pancreases. Circulating microparticles (MPs) were measured as surrogates of vascular cell injury. Vascular function was studied in mesenteric arterial rings.

RESULTS: Larger islets were twice as frequent in young rats versus middle-aged rats. In middle-aged rats there was a significant decrease of the β-cells/islet area ratio. Western blot analysis showed an increased expression of p53, p21, and p16 senescence markers (2-, 7- and 3-fold respectively) with no modification in caspase-3 activation. A 30% decrease of endothelial nitric oxide synthase (eNOS) was observed together with a 4-fold increase in TF expression. ROS formation increased significantly (2-fold) in middle-aged rats and their main source, determined by pharmacological inhibition, was NADPH oxidase and uncoupled nitric-oxide (NO) synthase. No sign of vascular injury (microparticles) or dysfunction was evidenced.

CONCLUSIONS: Modification in islet morphology and function were detected in middle-aged rats before any measurement of macro-vascular dysfunction. The data indicate a pancreatic senescence in the process of aging associated with uncontrolled accumulation of oxidative species that suggests a determining role of donor age in transplantation.

Keywords: Cell Aging, Cell-Derived Microparticles, Islets of Langerhans, tissue factor, Transplantation

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Annals of Transplantation eISSN: 2329-0358
Annals of Transplantation eISSN: 2329-0358