PROGENitors, TELomeres and ARTerial Aging (PROGENTELART)
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|ClinicalTrials.gov Identifier: NCT03928769|
Recruitment Status : Not yet recruiting
First Posted : April 26, 2019
Last Update Posted : April 26, 2019
The prevailing view in telomere epidemiology is that leukocyte telomere length (LTL) is associated with atherosclerotic cardiovascular disease (ACVD) since it serves as a biomarker of the cumulative burden of inflammation and oxidative stress during adult life. However, our recent results indicate that telomere length (TL) is mainly determined before adulthood, by TL at birth and TL attrition during growth. They also demonstrate that short telomeres precede the clinical manifestation of atherosclerosis. We therefore hypothesize that LT is not a simple marker, but a major determinant of arterial aging.
Two mechanistic hypotheses may explain an active role of short telomeres in accelerated arterial aging and development of ACVD.
The first is that a short TL at the leukocyte level reflects a short TL in endothelial progenitor cells (EPC). Cell replicative capacity being TL-dependent, short telomeres in the EPC would therefore be responsible for diminished replication capacity and vascular repair potential, thereby increasing the vulnerability for developing age-related arterial diseases.
The second hypothesis is that a short LTL reflects short TL in arterial wall cells, leading to an increase in the number of senescent vascular cells. Senescent cells are known to alter their secretion pattern, a phenomenon called senescence-associated secretory phenotype (SASP), and thus contribute to tissue injury by promoting inflammation and tissue remodeling leading to lesion progression.
These assumptions cannot be tested by LTL measurements alone. We propose, therefore, a model that makes it possible to examine different elements of TL dynamics in different tissues and cell types: leukocytes, circulating EPCs, in situ EPCs and arterial resident cells (mainly smooth muscle cells) in patients with or without atherosclerosis.
Our model is based on the following observations:
- TL is synchronized (equivalent) across somatic tissues/cells of the newborn: an individual with short telomeres (relative to his pairs) in one tissue should also have short telomeres (relative to his pairs) in other tissues.
- TL in EPCs (both circulating and in situ) determines the cell proliferative ability and therefore capacity for vessels repair during aging.
- TL in the cells of the arterial wall determines the number of senescent cells that therefore contribute to tissue injury through their change of phenotype.
The general aim of the present project is to examine the mechanistic links between arterial aging and TL in these different cell types.
|Condition or disease|
|Atherosclerosis of Artery|
|Study Type :||Observational [Patient Registry]|
|Estimated Enrollment :||100 participants|
|Target Follow-Up Duration:||1 Day|
|Official Title:||Role of Telomere Length in Arterial Smooth Muscle Cells and Circulating/Tissue Endothelial Progenitors in the Development of Atherosclerotic Lesions: Set up of the Experimental Model|
|Estimated Study Start Date :||April 20, 2019|
|Estimated Primary Completion Date :||April 20, 2021|
|Estimated Study Completion Date :||October 20, 2021|
Patients with traumatic vascular injury, ultimately corresponding to control patients
Patients will be included either in the atheromatous group (patients with atheromatous pathology) or in the control group (patients without atheromatous pathology), according to the clinical evaluation.
In the atheromatous group, subjects must have a clinically significant atheromatous pathology.
The investigator must specify the site (s) affected by the atheroma: carotid artery, coronary artery, aorta, renal artery, mesenteric artery or lower limb artery.
- Circulating EPC levels [ Time Frame: Inclusion visit ]Circulating EPC levels measured from whole blood specimens after primary culture of peripheral blood mononuclear cells (PBMC) on fibronectin (in cells per million of PBMCs)
- Tissue EPC levels [ Time Frame: Inclusion visit ]Tissue EPC levels measured from arterial wall cells in healthy and pathological zones obtained after enzymatic digestion, cell sorting and primary culture.
- TL in EPC [ Time Frame: Inclusion visit ]
Description and comparison of telomere lengths in circulating and tissue endothelial progenitors in patients with atheromatous pathology and those with traumatic vascular disease.
The telomere length in the different cell types (expressed in kb) will be measured by Southern blot after DNA extraction.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03928769
|Contact: Athanase BENETOS, PhD||+33 383 153 firstname.lastname@example.org|