Short telomeres protect from diet‐induced atherosclerosis in apolipoprotein E‐null mice

Abstract

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.

Aging and Atherosclerosis

“…78 Telomere length may therefore have functional consequences in aging and atherosclerosis. In contrast, whereas ectopic telomerase can maintain cell proliferation 23 and reverse the tissue degeneration in TERT-deficient mice, 79 reduction of telomerase activity in TERC Ϫ/Ϫ mice was found to be atheroprotective, 80 linked to decreased proliferative potential in macrophages and other inflammatory cells. These opposing findings suggest that telomerase activity may affect athero- Figure 2.…”

Short Telomere Length and Ischemic Heart Disease: Observational and Genetic Studies in 290 022 Individuals

“…Indeed, TERC and apolipoprotein E (APOE) knockout mice with critically short telomeres developed less atherosclerosis than controls with intact telomeres (27 ); however, mice models might not reflect an accurate model of human ischemic heart disease. Moreover, several studies suggest that telomerase Based on the CGPS and CCHS combined.…”

Role of Cellular Senescence in Lifestyle-Related Disease

“…In a mouse model of atherosclerosis, telomere shortening has been shown to decrease the area of atherosclerotic lesions, presumably because of the reduced proliferation of macrophages. 31 However, telomerase-deficient mice develop atherosclerotic plaques with a thin fibrous cap, suggesting that shortening of the telomeres in vascular cells may lead to plaque rupture in human atherosclerosis. Mice lacking telomerase activity develop hypertension in the 1st and 3rd generations as a result of an increased plasma endothelin-1 level caused by an overexpression of endothelinconverting enzyme.…”