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Aortic wall constitution in diabetes mellitus. A model to study protection of the abdominal aorta from aneurysmal degeneration

English title Aortic wall constitution in diabetes mellitus. A model to study protection of the abdominal aorta from aneurysmal degeneration
Applicant Diehm Nicolas
Number 121941
Funding scheme Project funding (Div. I-III)
Research institution Department for BioMedical Research Universität Bern
Institution of higher education University of Berne - BE
Main discipline Clinical Cardiovascular Research
Start/End 01.11.2008 - 30.04.2011
Approved amount 144'000.00
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All Disciplines (2)

Discipline
Clinical Cardiovascular Research
Clinical Endocrinology

Keywords (10)

aortic aneurysm; diabetes mellitus; aneurysmal aortic wall degeneration; matrix biology; basic histology; prevention of rupture; matrix changes; medical treatment; inflammation; matrix metalloproteinases

Lay Summary (English)

Lead
Lay summary
Aim of the projectThis project is aimed at providing insights on histological and protein expression differences of the aortic wall between diabetic and non-diabetic subjects. These findings might shed light on mechanisms responsible for the lower prevalence and slower progression of AAA in diabetic patients and might have the potential to lay the foundations for the discovery of new molecular targets.Background of the projectRisk of abdominal aortic aneurysm (AAA) considerably increases with age, and is particularly prevalent in males and in smokers 1-4. Meanwhile, AAA is the 10th most common cause of death in elderly males, and with increased aging of Western civilizations, AAA has become a relevant socioeconomic health care problem.In contrast to our understanding on its high prevalence, there still is little progress in therapeutic options for the prevention of disease evolution and progression. Various classes of drugs ranging from antibiotics to antihypertensive agents have been tested, but none was clearly shown to definitely prevent AAA progression 5,6. Thus, small AAAs are currently followed until they are large enough to be repaired by surgical or endovascular means.Interestingly there are consistent epidemiologic findings that diabetes mellitus (DM) has a strong protective effect on both the prevalence and the progression of aneurysmal disease 2-4,7-12. Whether diabetic and non-diabetic individuals differ in abdominal aortic wall constitution or whether other factors are more relevant is unclear, however, might help to further clarify pathophysiology and invent novel pharmacological options. Of note, whereas proteolysis and matrix destruction are characteristics of aneurysmal disease, it is the increased matrix volume that is characteristic for diabetic angiopathy and that might also be the case in the abdominal aorta 13,14. Despite these observations, assessment of these differences has drawn little attention in AAA research. Experimental methodsAortic wall biopsies will be harvested from corpses of diabetic and non-diabetic subjects, 40 to 60 years of age, without AAA (hypotheses 1-3) and with small AAA (hypothesis 4) undergoing autopsy at the departments of pathology and forensic medicine, University Bern within <6 hours after death has been determined. Samples harvested according to a standardized protocol 15 will be assessed with regard to media thickness, number of intact elastic lamellar units, medial destruction grade, and expression of connective tissue growth factor (CTGF) using standard histology and immunohistochemistry. Furthermore, a broad screening of expression of >900 proteins will be performed using a proteomic assay. Results will be stratified according to the smoking or non-smoking status of diabetic and non-diabetic subjects during life.HypothesesIn corpses from patients with non-aneurysmal aorta as well as in those of patients with small (3-4.5) abdominal aortic aneurysm (AAA) .....… the infrarenal aortic wall has a higher media thickness, number of elastic lamellae, extracellular matrix deposition (represented by expression of CTGF and collagen) in diabetic as compared with non-diabetic middle-aged subjects.... substantial differences in protein expression exist comparing aortic wall tissue of corpses with DM to that of corpses without DM.... significant differences in the expression of proteins associated with the pathophysiology of AAA can be found comparing diabetic with non-diabetic samples.….. the aortic wall expression of proteins associated with DM affects basic biological functions of SMC.
Direct link to Lay Summary Last update: 21.02.2013

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