Dataset Information

MicroRNAs mediate the senescence-associated decline of NRF2 in endothelial cells.

ABSTRACT: Oxidative stress predisposes to several aging-associated diseases, such as cardiovascular diseases and cancer. In aging, increase in the production of reactive oxygen species is typically accompanied with a decline in adaptive stress responses to oxidative stress. The decline is primarily due to a decrease in antioxidant production. Nuclear factor E2-Related Factor 2 (NRF2) is a key transcription factor regulating oxidative and electrophilic stress responses, but it has also been shown to play a role in the regulation of cell metabolism. NRF2 expression declines in aging, but the mechanisms remain unclear. In this study, we show that microRNAs (miRNAs) that are abundant in old endothelial cells decrease NRF2 expression by direct targeting of NRF2 mRNA. The effect is reversed by miRNA inhibition. The senescence-associated downregulation of NRF2 decreases endothelial glycolytic activity and stress tolerance both of which are restored after reinstating NRF2. Manipulation of the senescence-associated miRNA levels affects the glycolytic activity and stress tolerance consistently with the NRF2 results. We conclude that senescence-associated miRNAs are involved in the decline of NRF2 expression, thus contributing to the repression of adaptive responses during cell senescence.

SUBMITTER: Kuosmanen SM

PROVIDER: S-EPMC6037909 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

MicroRNAs mediate the senescence-associated decline of NRF2 in endothelial cells.

Kuosmanen Suvi M SM Sihvola Virve V Kansanen Emilia E Kaikkonen Minna U MU Levonen Anna-Liisa AL

Redox biology 20180622

Oxidative stress predisposes to several aging-associated diseases, such as cardiovascular diseases and cancer. In aging, increase in the production of reactive oxygen species is typically accompanied with a decline in adaptive stress responses to oxidative stress. The decline is primarily due to a decrease in antioxidant production. Nuclear factor E2-Related Factor 2 (NRF2) is a key transcription factor regulating oxidative and electrophilic stress responses, but it has also been shown to play a ...[more]

PMID: 29986211

Similar Datasets

Project description:Despite the decline in their proliferative potential, senescent cells display a high metabolic activity. Senescent cells have been shown to acquire a more glycolytic state even in presence of high oxygen levels, in a way similar to cancer cells. The diversion of pyruvate, the final product of glycolysis, away from oxidative phosphorylation results in an altered bioenergetic state and may occur as a response to the enhanced oxidative stress caused by the accumulation of dysfunctional mitochondria. This metabolic shift leads to increased AMP/ATP and ADP/ATP ratios, to the subsequent AMPK activation, and ultimately to p53-mediated growth arrest. Mounting evidences suggest that metabolic reprogramming is critical to direct considerable amounts of energy toward specific activities related to the senescent state, including the senescence-associated secretory phenotype (SASP) and the modulation of immune responses within senescent cell tissue microenvironment. Interestingly, despite the relative abundance of oxygen in the vascular compartment, healthy endothelial cells (ECs) produce most of their ATP content from the anaerobic conversion of glucose to lactate. Their high glycolytic rate further increases during senescence. Alterations in EC metabolism have been identified in age-related diseases (ARDs) associated with a dysfunctional vasculature, including atherosclerosis, type 2 diabetes and cardiovascular diseases. In particular, higher production of reactive oxygen species deriving from a variety of enzymatic sources, including uncoupled endothelial nitric oxide synthase and the electron transport chain, causes DNA damage and activates the NAD+-consuming enzymes polyADP-ribose polymerase 1 (PARP1). These non-physiological mechanisms drive the impairment of the glycolytic flux and the diversion of glycolytic intermediates into many pathological pathways. Of note, accumulation of senescent ECs has been reported in the context of ARDs. Through their pro-oxidant, pro-inflammatory, vasoconstrictor, and prothrombotic activities, they negatively impact on vascular physiology, promoting both the onset and development of ARDs. Here, we review the current knowledge on the cellular senescence-related metabolic changes and their contribution to the mechanisms underlying the pathogenesis of ARDs, with a particular focus on ECs. Moreover, current and potential interventions aimed at modulating EC metabolism, in order to prevent or delay ARD onset, will be discussed.

Dataset Information

MicroRNAs mediate the senescence-associated decline of NRF2 in endothelial cells.

Publications

MicroRNAs mediate the senescence-associated decline of NRF2 in endothelial cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets