Abstract
Aging is associated with an increased risk of cardiovascular disease. Numerical and functional declines in endothelial progenitor cells (EPCs) limit their capacity for endothelial repair and promote the development of cardiovascular disease. We explored the effects of nuclear factor (erythroid-derived 2)-like 2 (NRF2) on EPC activity during aging. Both in vitro and in vivo, the biological functioning of EPCs decreased with aging. The expression of NRF2 and its target genes (Ho-1, Nqo-1 and Trx) also declined with aging, while Nod-like receptor protein 3 (NLRP3) expression increased. Aging was associated with oxidative stress, as evidenced by increased reactive oxygen species and malondialdehyde levels and reduced superoxide dismutase activity. Nrf2 silencing impaired the functioning of EPCs and induced oxidative stress in EPCs from young mice. On the other hand, NRF2 activation in EPCs from aged mice protected these cells against oxidative stress, ameliorated their biological dysfunction and downregulated the NLRP3 inflammasome. These findings suggest NRF2 can prevent the functional damage of EPCs and downregulate the NLRP3 inflammasome through NF-κB signaling.
Highlights
With the increased longevity of humans, the percentage of people entering the 65-and-older age group is increasing rapidly, and this trend is expected to continue for several decades
These data indicated that the migration, proliferation, angiogenesis and secretion functions of endothelial progenitor cells (EPCs) all decline during aging
We found that age-related loss of nuclear factor (erythroid-derived 2)-like 2 (NRF2) expression reduced the functioning of EPCs and thereby impaired angiogenesis
Summary
With the increased longevity of humans, the percentage of people entering the 65-and-older age group is increasing rapidly, and this trend is expected to continue for several decades. Aging is the most important independent risk factor for CVD, due to its remarkable effects on the heart and arterial system. Aging cardiovascular tissues undergo a series of pathological changes, including hypertrophy, altered left ventricular diastolic function, a diminished left ventricular systolic reverse capacity, increased arterial stiffness and impaired endothelial function [1,2,3]. The reduced endothelial function with aging contributes to the development of CVD, so maintaining the normal endothelial integrity is an important therapeutic approach to reduce the agerelated risk of CVD. Endothelial progenitor cells (EPCs) are thought to promote postnatal neovascularization and maintain endothelial integrity and function. These cells have aroused the interest of researchers, especially given the limited regenerative capacity of mature endothelial cells. It has been suggested that EPCs foster the continuous recovery of the endothelium after injury/damage, and stimulate angiogenesis [4]
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