Reduced NRF2 expression suppresses endothelial progenitor cell function and induces senescence during aging

Area of Science:

• Cardiovascular Biology
• Cellular Aging
• Molecular Medicine

Background:

• Aging diminishes endothelial progenitor cell (EPC) number and function, contributing to cardiovascular disease.
• Declines in EPCs impair vascular repair mechanisms.
• Oxidative stress and inflammation are key factors in age-related cardiovascular dysfunction.

Purpose of the Study:

• To investigate the role of nuclear factor (erythroid-derived 2)-like 2 (NRF2) in regulating EPC activity during aging.
• To determine if NRF2 modulation can counteract age-associated EPC dysfunction.
• To elucidate the molecular mechanisms, including NLRP3 inflammasome signaling, involved in NRF2's effects on EPCs.

Main Methods:

• In vitro and in vivo studies assessing EPC function in young and aged mice.
• Analysis of NRF2, its target genes (Ho-1, Nqo-1, Trx), and NLRP3 inflammasome expression.
• Evaluation of oxidative stress markers (ROS, MDA, SOD activity).
• Experimental manipulation of Nrf2 expression (silencing and activation) in EPCs.

Main Results:

• EPC function and NRF2 pathway activity decreased with age, while NLRP3 expression increased.
• Aging was characterized by elevated oxidative stress markers.
• Nrf2 silencing in young EPCs mimicked aging-related dysfunction and oxidative stress.
• NRF2 activation in aged EPCs restored function, reduced oxidative stress, and downregulated NLRP3 inflammasome.

Conclusions:

• NRF2 plays a critical protective role in maintaining EPC function during aging.
• NRF2 activation mitigates age-associated EPC dysfunction and oxidative stress.
• NRF2 downregulates the NLRP3 inflammasome, potentially via NF-κB signaling, offering a therapeutic target for age-related cardiovascular disease.