Abstract
Senescent endothelial cells (EC) have been identified in cardiovascular disease, in angiogenic tumour associated vessels and in aged individuals. We have previously identified a novel anti-inflammatory senescent phenotype of EC. We show here that caveolae are critical in the induction of this anti-inflammatory senescent state. Senescent EC induced by either the overexpression of ARHGAP18/SENEX or by H2O2 showed significantly increased numbers of caveolae and associated proteins Caveolin-1, cavin-1 and cavin-2. Depletion of these proteins by RNA interference decreased senescence induced by ARHGAP18 and by H2O2. ARHGAP18 overexpression induced a predominantly anti-inflammatory senescent population and depletion of the caveolae-associated proteins resulted in the preferential reduction in this senescent population as measured by neutrophil adhesion and adhesion protein expression after TNFα treatment. In confirmation, EC isolated from the aortas of CAV-1−/− mice failed to induce this anti-inflammatory senescent cell population upon expression of ARHGAP18, whereas EC from wild-type mice showed a significant increase. NF-κB is one of the major transcription factors mediating the induction of E-selectin and VCAM-1 expression, adhesion molecules responsible for leucocyte attachment to EC. TNFα-induced activation of NF-κB was suppressed in ARHGAP18-induced senescent EC, and this inhibition was reversed by Caveolin-1 knock-down. Thus, out results demonstrate that an increase in caveolae and its component proteins in senescent ECs is associated with inhibition of the NF-kB signalling pathway and promotion of the anti-inflammatory senescent pathway.
Highlights
Senescence plays a major role in many pathophysiological processes (Adams, 2009; Rodier & Campisi, 2011), including tumour suppressionAccepted for publication 24 August 2014(Collado & Serrano, 2010), inhibition of liver damage (Krizhanovsky et al, 2008), and it is linked to the progression of aging and age-related pathologies (Erusalimsky & Kurz, 2005)
We have previously reported that ARHGAP18 overexpression induced senescence in endothelial cells (EC) (ARHGAP18-senescent EC) (Coleman et al, 2010)
To investigate the mechanism underlying the induction of the antiinflammatory phenotype, we first investigated the morphology of the enlarged ARHGAP18-senescent EC by electron microscopy (EM)
Summary
(Collado & Serrano, 2010), inhibition of liver damage (Krizhanovsky et al, 2008), and it is linked to the progression of aging and age-related pathologies (Erusalimsky & Kurz, 2005). Senescence involves the permanent inhibition of cell cycle progression and the induction of a pattern of gene expression and secretion of factors referred to as the senescence associated secretory phenotype (SASP) (Coppe et al, 2010; Freund et al, 2010). Accumulation of senescent cells seen in aged mice may, through secretion of the SASP, contribute to low-level chronic inflammation, a phenotype common to age-related pathologies (Erusalimsky & Kurz, 2005; Minamino & Komuro, 2007; Freund et al, 2010). Baker et al demonstrated that specific inactivation of senescent cells in BubR1 progeroid mice can delay premature aging and age-related diseases (Baker et al, 2008)
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