A comparison of replicative senescence and doxorubicin-induced premature senescence of vascular smooth muscle cells isolated from human aorta

Abstract

Senescence of vascular smooth muscle cells (VSMCs) contributes to aging as well as age-related diseases of the cardiovascular system. Senescent VSMCs have been shown to be present in atherosclerotic plaques. Both replicative (RS) and stress-induced premature senescence (SIPS) accompany cardiovascular diseases. We aimed to establish the signature of RS and SIPS of VSMCs, induced by a common anticancer drug, doxorubicin, and to discover the so far undisclosed features of senescent cells that are potentially harmful to the organism. Most of the senescence hallmarks were common for both RS and SIPS; however, some differences were observed. 32 % of doxorubicin-treated cells were arrested in the G2/M phase of the cell cycle, while 73 % of replicatively senescing cells were arrested in the G1 phase. Moreover, on the basis of alkaline phosphatase activity measurements, we show that a 7-day treatment with doxorubicin (dox), does not cause precocious cell calcification, which is a characteristic feature of RS. We did not observe calcification even though after 7 days of dox-treatment many other markers characteristic for senescent cells were present. It can suggest that dox-induced SIPS does not accelerate the mineralization of vessels. We consider that detailed characterization of the two types of cellular senescence can be useful in in vitro studies of potential anti-aging factors.Electronic supplementary materialThe online version of this article (doi:10.1007/s10522-013-9477-9) contains supplementary material, which is available to authorized users.

Doxorubicin‐induced cardiomyocyte toxicity – protective effects of endothelial cells in a tri‐culture model system

“…We further demonstrate the dose‐dependent reduction in doxorubicin‐induced CMC toxicity when tri‐cultured with ECs and SMCs, in particular when grown under flow conditions, in a 3D environment. While the dose‐dependent cumulative toxicity of doxorubicin is well documented for CMCs, we also demonstrate a significant dose‐dependent reduction in EC and SMC numbers (Wojcik et al, ; Bielak‐Zmijewska et al, ). Doxorubicin‐induced EC apoptosis and disturbed crosstalk between ECs and CMCs has recently been demonstrated using VEGF‐B gene therapy in a murine model (Rasanen et al, ).…”

Tissue-Engineered Vascular Grafts Created From Human Induced Pluripotent Stem Cells

“…The reasons for the extensive calcification that we observed using cells with shortened telomeres and abnormal karyotype also remain unclear, but one of the hallmarks of replicative senescence (RS) is calcification. Studies have revealed increased alkaline phosphatase activity (a key protein involved in matrix calcification) during RS of cultured vascular SMCs [40, 41]. Another explanation might involve the neural crest origin of the derived cells, which is known to be prone to calcification [42].…”

Czym jest i czym nie jest starzenie komórki?

“…Interestingly, the number of population doublings in case of replicative senescence appear to vary, depending on the cell type and cell culture conditions. For example, human peritoneal mesothelial cells were found to reach, on average, six population doublings before senescence [Ksiazek et al, 2006], whereas this number for human vascular smooth muscle cells (VSMCs), thoroughly studied by us, exceeded thirty, what usually takes several months [Bielak-Zmijewska et al, 2014]. Interestingly, we have shown that VSMCs undergoing replicative senescence are arrested in the G1, but those undergoing SIPS, in the G1 and G2/M phase of the cell cycle.…”

“…We have shown that replicatively, but not prematurely (i.e. undergoing SIPS), senescing human vascular smooth muscle cells have shorter telomeres [Bielak-Zmijewska et al, 2014]. However, SIPS can affect the level of the shelterin proteins, which protect the structure of telomeres.…”

“…Interestingly, we have shown that VSMCs undergoing replicative senescence are arrested in the G1, but those undergoing SIPS, in the G1 and G2/M phase of the cell cycle. Another difference between replicative senescence and SIPS concerns mineralization, which is typical only for replicative senescence of VSMCs [Bielak-Zmijewska et al, 2014]. Some time ago it was postulated that we are ageing due to senescence of our cells [Campisi 2001].…”