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NOX4 downregulation leads to senescence of human vascular smooth muscle cells
Dorota Przybylska1, Dorota Janiszewska1, Aleksandra Goździk1
1Laboratory of Molecular Bases of Aging, Department of Biochemistry, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland.
Abstract:
Senescence is a stress response characterized by an irreversible growth arrest and alterations in certain cell functions. It is believed that both double-strand DNA breaks (DSB) and increased ROS level are the main culprit of senescence. Excessive ROS production is also particularly important in the development of a number of cardiovascular disorders. In this context the involvement of professional ROS-producing enzymes, NADPH oxidases (NOX), was postulated. In contrary to the common knowledge, we have shown that not only increased ROS production but also diminished ROS level could be involved in the induction of senescence.Accordingly, our studies revealed that stress-induced premature senescence (SIPS) of vascular smooth muscle cells (VSMCs) induced by doxorubicin or H2O2, correlates with increased level of DSB and ROS. On the other hand, both SIPS and replicative senescence were accompanied by diminished expression of NOX4. Moreover, inhibition of NOX activity or decrease of NOX4 expression led to permanent growth arrest of VSMCs and secretion of interleukins and VEGF. Interestingly, cells undergoing senescence due to NOX4 depletion neither acquired DSB nor activated DNA damage response. Instead, transient induction of the p27, upregulation of HIF-1alpha, decreased expression of cyclin D1 and hypophosphorylated Rb was observed. Our results showed that lowering the level of ROS-producing enzyme - NOX4 oxidase below physiological level leads to cellular senescence of VSMCs which is correlated with secretion of pro-inflammatory cytokines. Thus the use of specific NOX4 inhibitors for pharmacotherapy of vascular diseases should be carefully considered.
Insights
Cellular senescence, a state of irreversible growth arrest, can be triggered by both high and low reactive oxygen species (ROS) levels. This study reveals that reduced NOX4 oxidase activity induces senescence in vascular cells, impacting cardiovascular disease therapies.
Area of Science:
- Cell Biology
- Molecular Biology
- Cardiovascular Research
Background:
- Cellular senescence is a stress response involving irreversible growth arrest and functional changes.
- Double-strand DNA breaks (DSB) and elevated reactive oxygen species (ROS) are traditionally linked to senescence.
- NADPH oxidases (NOX) are key enzymes in ROS production, implicated in cardiovascular disorders.
Purpose of the Study:
- To investigate the role of ROS levels, specifically NOX4, in cellular senescence.
- To determine if diminished ROS levels, rather than increased levels, can induce senescence.
- To explore the mechanisms underlying NOX4-mediated senescence in vascular smooth muscle cells (VSMCs).
Main Methods:
- Induction of stress-induced premature senescence (SIPS) in VSMCs using doxorubicin or H2O2.
- Assessment of DSB, ROS levels, and NOX4 expression.
- Inhibition of NOX activity and NOX4 expression.
- Analysis of cell cycle regulators (p27, cyclin D1, Rb) and signaling pathways (HIF-1alpha).
- Measurement of secreted cytokines (interleukins, VEGF).
Main Results:
- SIPS induced by doxorubicin or H2O2 correlated with increased DSB and ROS.
- Both SIPS and replicative senescence were associated with decreased NOX4 expression.
- Inhibition of NOX activity or NOX4 depletion caused permanent VSMC growth arrest and secretion of interleukins and VEGF.
- NOX4 depletion-induced senescence occurred without DSB or DNA damage response, but involved p27 induction, HIF-1alpha upregulation, decreased cyclin D1, and hypophosphorylated Rb.
- Lowering NOX4 levels below physiological levels induced VSMC senescence and pro-inflammatory cytokine secretion.
Conclusions:
- Reduced ROS levels, specifically due to diminished NOX4 oxidase activity, can induce cellular senescence in VSMCs.
- NOX4-dependent senescence differs mechanistically from DSB-induced senescence, involving cell cycle alterations without DNA damage.
- The findings suggest careful consideration of NOX4 inhibitors in treating vascular diseases due to their potential to induce senescence.
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