Short telomeres protect from diet-induced atherosclerosis in apolipoprotein E-null mice.
By imposing a replicative defect in most somatic cells, gradual telomere attrition during aging is thought to progressively impair cellular function and viability and may contribute to age-related disease. Immune cells play important roles in all phases of atherosclerosis, a multifactorial disease that prevails within the elderly. Because shorter telomeres have been found in circulating blood leukocytes of human patients with advanced coronary atherosclerosis, it has been suggested that telomere shortening may predispose the organism to atheroma development. In this study, we assessed the impact of telomere attrition on atherogenesis induced by dietary cholesterol in apolipoprotein E (apoE)-deficient mice, a well-established model of experimental atherosclerosis that recapitulates important aspects of the human disease. Our study shows that late-generation mice doubly deficient in apoE and telomerase RNA experience telomere attrition and a substantial reduction of atherosclerosis compared with control mice with intact telomerase, in spite of sustained hypercholesterolemia in response to the atherogenic diet. Short telomeres impaired the proliferation of both lymphocytes and macrophages, an important step in atherosclerosis development. Therefore, telomere exhaustion resulting in replicative immunosenescence may serve as a mechanism for restricting atheroma progression.
Poch
Enric
E
Laboratory of Vascular Biology, Department of Molecular and Cellular Pathology and Therapy, Instituto de Biomedicina de Valencia-CSIC, Valencia 46010, Spain.
Carbonell
Paz
P
Franco
Sonia
S
Díez-Juan
Antonio
A
Blasco
María A
MA
Andrés
Vicente
V
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002455:Cell Division; D002791:Cholesterol, Dietary / Q000494:pharmacology*; D004032:Diet; D005260:Female; D017353:Gene Deletion; D007962:Leukocytes / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012313:RNA / Q000235:genetics; D012727:Sex Characteristics; D019098:Telomerase / Q000172:deficiency / Q000235:genetics; D016615:Telomere / Q000378:metabolism*
D001057:Apolipoproteins E; D002791:Cholesterol, Dietary; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase