NOX4 downregulation leads to senescence of human vascular smooth muscle cells.

Dorota Przybylska,Grażyna Mosieniak,Ewa Sikora,Aleksandra Goździk,Piotr Sunderland,Anna Bielak-Zmijewska,Dorota Janiszewska

doi:10.18632/oncotarget.12079

Dorota Przybylska, Grażyna Mosieniak + Show 5 more

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https://doi.org/10.18632/oncotarget.12079

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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.

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Cellular senescence is a stress response that leads to irreversible cell cycle arrest accompanied by a set of distinct phenotypic and functional changes
As one of the features of senescence is the senescence-associated secretory phenotype (SASP) we investigated the level of interleukin 6 (IL-6), 8 (IL-8) and vascular endothelial growth factor (VEGF) secreted after 6 days of Human primary vascular smooth muscle cells (hVSMCs) treatment with dox or H2O2 (Figure 1C)
The data presented here show for the first time that the decreasing of the expression of ROS-producing NADPH oxidase, NOX4 in human vascular smooth muscle cells leads to permanent growth arrest

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Cellular senescence is a stress response that leads to irreversible cell cycle arrest accompanied by a set of distinct phenotypic and functional changes. The general biological role of senescence is to eliminate damaged or unwanted cells, the outcome of it could be either beneficial or detrimental depending on the cellular and tissue context [5]. One of the most commonly recognized is telomere shortening that progresses gradually with each cell division and leads to so-called replicative senescence [6]. In contrast to gradual exhaustion of proliferation potential, cellular senescence could be induced within short time by stress factors [7]. Among these factors ROS have been considered as the most common. ROS have been shown to activate or inhibit kinases, phosphatases as well as transcription factors involved in regulation of prosurvival pathways, proliferation, differentiation and metabolism [10, 11]

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