Telomeres, atherosclerosis, and the hemothelium: the longer view

Abstract

The model we propose to explain the links between atherosclerosis and telomere dynamics (birth telomere length and its age-dependent shortening) in leukocytes takes cues from three facts: atherosclerosis is a disease of the vascular endothelium; the hematopoietic system and the vascular endothelium share a common embryonic origin; interindividual variation in leukocyte telomere length (LTL) in the general population has a genetic explanation. The model posits that LTL dynamics mirror telomere dynamics in hematopoietic stem cells (HSCs), where telomere length is an index of HSC reserves. Diminished HSC reserves at birth, their accelerated attrition rate afterward, or both are are reflected in shortened LTL during adulthood-a phenomenon that confers increased risk for atherosclerosis. We explain how telomere length in HSCs serves as both a biomarker of atherosclerosis and a determinant of its development. Our model comes down to this proposition: Shortened LTL predicts increased atherosclerotic risk because the injurious component of atherosclerosis exceeds the repair capacity of HSC reserves, which largely depend on HSC telomere length.

Figure 1

Overall model linking the hematopoietic stem cell (HSC) reserves with atherosclerosis. Atherosclerosis is partially the outcome of demand for repair, exerted by injury to the vascular endothelium on the HSC reserves. The repair arm of the HSC reserves is mediated by endothelial progenitor cells, and the size of these reserves is expressed in leukocyte telomere length. Both genetic and environmental factors continuously impact the injury/repair processes.