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vascular smooth muscle cell senescence and DNA damage

Julie Wang, Anna K Uryga, Johannes Reinhold, Nichola Figg, Lauren Baker, Alison Finigan, Kelly Gray, Sheetal Kumar, Murray Clarke, Martin Bennett
BACKGROUND: Although vascular smooth muscle cell (VSMC) proliferation is implicated in atherogenesis, VSMCs in advanced plaques and cultured from plaques show evidence of VSMC senescence and DNA damage. In particular, plaque VSMCs show shortening of telomeres, which can directly induce senescence. Senescence can have multiple effects on plaque development and morphology; however, the consequences of VSMC senescence or the mechanisms underlying VSMC senescence in atherosclerosis are mostly unknown...
November 17, 2015: Circulation
Andrew R Mendelsohn, James W Larrick
Reduced telomere length with increasing age in dividing cells has been implicated in contributing to the pathologies of human aging, which include cardiovascular and metabolic disorders, through induction of cellular senescence. Telomere shortening results from the absence of telomerase, an enzyme required to maintain telomere length. Telomerase reverse transcriptase (TERT), the protein subunit of telomerase, is expressed only transiently in a subset of adult somatic cells, which include stem cells and smooth muscle cells...
October 2015: Rejuvenation Research
Anna K Uryga, Martin R Bennett
Atherosclerosis is a disease of ageing in that its incidence and prevalence increase with age. However, atherosclerosis is also associated with biological ageing, manifest by a number of typical hallmarks of ageing in the atherosclerotic plaque. Thus, accelerated biological ageing may be superimposed on the effects of chronological ageing in atherosclerosis. Tissue ageing is seen in all cells that comprise the plaque, but particularly in vascular smooth muscle cells (VSMCs). Hallmarks of ageing include evidence of cell senescence, DNA damage (including telomere attrition), mitochondrial dysfunction, a pro-inflammatory secretory phenotype, defects in proteostasis, epigenetic changes, deregulated nutrient sensing, and exhaustion of progenitor cells...
April 15, 2016: Journal of Physiology
D T Warren, T Tajsic, L J Porter, R M Minaisah, A Cobb, A Jacob, D Rajgor, Q P Zhang, C M Shanahan
Prelamin A accumulation and persistent DNA damage response (DDR) are hallmarks of vascular smooth muscle cell (VSMC) ageing and dysfunction. Although prelamin A is proposed to interfere with DNA repair, our understanding of the crosstalk between prelamin A and the repair process remains limited. The extracellular signal-regulated kinases 1 and 2 (ERK1/2) have emerged as key players in the DDR and are known to enhance ataxia telangiectasia-mutated protein (ATM) activity at DNA lesions, and in this study, we identified a novel relationship between prelamin A accumulation and ERK1/2 nuclear compartmentalisation during VSMC ageing...
September 2015: Cell Death and Differentiation
Wioleta Grabowska, Karolina Kucharewicz, Maciej Wnuk, Anna Lewinska, Małgorzata Suszek, Dorota Przybylska, Grazyna Mosieniak, Ewa Sikora, Anna Bielak-Zmijewska
Curcumin is considered not only as a supplement of the diet but also as a drug in many types of diseases and even as a potential anti-aging compound. It can reduce inflammation that increases with age and accompanies almost all age-related diseases. It has been suggested that curcumin can play a beneficial role in the cardiovascular system. However, there are also data showing that curcumin can induce senescence in cancer cells, which is a beneficial effect in cancer therapy but an undesirable one in the case of normal cells...
February 2015: Age (2005-)
Kelly Gray, Sheetal Kumar, Nichola Figg, James Harrison, Lauren Baker, John Mercer, Trevor Littlewood, Martin Bennett
RATIONALE: DNA damage and the DNA damage response have been identified in human atherosclerosis, including in vascular smooth muscle cells (VSMCs). However, although double-stranded breaks (DSBs) are hypothesized to promote plaque progression and instability, in part, by promoting cell senescence, apoptosis, and inflammation, the direct effects of DSBs in VSMCs seen in atherogenesis are unknown. OBJECTIVE: To determine the presence and effect of endogenous levels of DSBs in VSMCs on atherosclerosis...
February 27, 2015: Circulation Research
Olga Alster, Anna Bielak-Zmijewska, Grazyna Mosieniak, Maria Moreno-Villanueva, Wioleta Dudka-Ruszkowska, Aleksandra Wojtala, Monika Kusio-Kobiałka, Zbigniew Korwek, Alexander Burkle, Katarzyna Piwocka, Jan K Siwicki, Ewa Sikora
Nibrin plays an important role in the DNA damage response (DDR) and DNA repair. DDR is a crucial signaling pathway in apoptosis and senescence. To verify whether truncated nibrin (p70), causing Nijmegen Breakage Syndrome (NBS), is involved in DDR and cell fate upon DNA damage, we used two (S4 and S3R) spontaneously immortalized T cell lines from NBS patients, with the founding mutation and a control cell line (L5). S4 and S3R cells have the same level of p70 nibrin, however p70 from S4 cells was able to form more complexes with ATM and BRCA1...
2014: PloS One
Miho Suzuki, Akari Minami, Atsuko Nakanishi, Keiko Kobayashi, Satoru Matsuda, Yasunori Ogura, Yasuko Kitagishi
Atherosclerosis, the major cause of heart attack and stroke, is a chronic inflammatory disease characterized by the formation of atherosclerotic plaque. Oxidized low-density lipoprotein through increased oxidative stress has been identified as one of the primary factors responsible for atherogenesis. Cell proliferation and death are key processes in the progression of atherosclerosis. The oxidative environment in areas of lipid accumulation is mainly created by the production of reactive oxygen species, which are assumed to mediate vascular tissue injury...
October 2014: International Journal of Molecular Medicine
Pavan B Narayanaswamy, Mahshid Hodjat, Hermann Haller, Inna Dumler, Yulia Kiyan
DNA damage induced by numerous exogenous or endogenous factors may have irreversible consequences on the cell leading to cell cycle arrest, senescence and cell death. The DNA damage response (DDR) is powerful signaling machinery triggered in response to DNA damage, to provide DNA damage recognition, signaling and repair. Most anticancer drugs induce DNA damage, and DNA repair in turn attenuates therapeutic efficiency of those drugs. Approaches delaying DNA repair are often used to increase efficiency of treatment...
2014: PloS One
Yiwen Liu, Ignat Drozdov, Rukshana Shroff, Leilani E Beltran, Catherine M Shanahan
RATIONALE: Vascular calcification is prevalent in the aging population, yet little is known of the mechanisms driving age-associated vascular smooth muscle cell (VSMC) phenotypic change. OBJECTIVE: To investigate the role of nuclear lamina disruption, a specific hallmark of VSMC aging, in driving VSMC osteogenic differentiation. METHODS AND RESULTS: Prelamin A, the unprocessed form of the nuclear lamina protein lamin A, accumulated in calcifying human VSMCs in vitro and in vivo, and its overexpression promoted VSMC osteogenic differentiation and mineralization...
May 10, 2013: Circulation Research
Isabelle Gorenne, Sheetal Kumar, Kelly Gray, Nichola Figg, Haixiang Yu, John Mercer, Martin Bennett
BACKGROUND: Vascular smooth muscle cells (VSMCs) in human atherosclerosis manifest extensive DNA damage and activation of the DNA damage response, a pathway that coordinates cell cycle arrest and DNA repair, or can trigger apoptosis or cell senescence. Sirtuin 1 deacetylase (SIRT1) regulates cell ageing and energy metabolism and regulates the DNA damage response through multiple targets. However, the direct role of SIRT1 in atherosclerosis and how SIRT1 in VSMCs might regulate atherosclerosis are unknown...
January 22, 2013: Circulation
Chiara Armani, Nicoletta Botto, Maria Grazia Andreassi, Emilio Centaro
There is increasing evidence that an elevation of oxidative stress and associated oxidative damages are mediators of vascular injury in various cardiovascular pathologies, including hypertension. Accumulation of oxidative damage is thought to play an important role in aging and age-associated diseases such as hypertension and oxidative stress may function as a common trigger for activation of the senescence programme. In this regard, the role of telomeres in the onset, development and prognosis of hypertension has generated considerable interest...
2013: Current Pharmaceutical Design
Juhee Han, Panagiotis Mistriotis, Pedro Lei, Dan Wang, Song Liu, Stelios T Andreadis
Although the therapeutic potential of mesenchymal stem cells (MSCs) is widely accepted, loss of cell function due to donor aging or culture senescence are major limiting factors hampering their clinical application. Our laboratory recently showed that MSCs originating from older donors suffer from limited proliferative capacity and significantly reduced myogenic differentiation potential. This is a major concern, as the patients most likely to suffer from cardiovascular disease are elderly. Here we tested the hypothesis that a single pluripotency-associated transcription factor, namely Nanog, may reverse the proliferation and differentiation potential of bone marrow-derived MSC (BM-MSC) from adult donors...
December 2012: Stem Cells
Matej Durik, Maryam Kavousi, Ingrid van der Pluijm, Aaron Isaacs, Caroline Cheng, Koen Verdonk, Annemarieke E Loot, Hisko Oeseburg, Usha Musterd Bhaggoe, Frank Leijten, Richard van Veghel, René de Vries, Goran Rudez, Renata Brandt, Yanto R Ridwan, Elza D van Deel, Martine de Boer, Dennie Tempel, Ingrid Fleming, Gary F Mitchell, Germaine C Verwoert, Kirill V Tarasov, Andre G Uitterlinden, Albert Hofman, Henricus J Duckers, Cornelia M van Duijn, Ben A Oostra, Jacqueline C M Witteman, Dirk J Duncker, A H Jan Danser, Jan H Hoeijmakers, Anton J M Roks
BACKGROUND: Vascular dysfunction in atherosclerosis and diabetes mellitus, as observed in the aging population of developed societies, is associated with vascular DNA damage and cell senescence. We hypothesized that cumulative DNA damage during aging contributes to vascular dysfunction. METHODS AND RESULTS: In mice with genomic instability resulting from the defective nucleotide excision repair genes ERCC1 and XPD (Ercc1(d/-) and Xpd(TTD) mice), we explored age-dependent vascular function compared with that in wild-type mice...
July 24, 2012: Circulation
Li-Juan Min, Masaki Mogi, Jun Iwanami, Fei Jing, Kana Tsukuda, Kousei Ohshima, Masatsugu Horiuchi
Angiotensin II type 2 (AT(2)) receptor-interacting protein (ATIP), which interacts with the C-terminal tail of the AT(2) receptor, regulates the functions of the AT(2) receptor. We have reported that AT(2) receptor stimulation attenuated vascular senescence. Therefore, we examined the possible negative role of ATIP in regulating vascular senescence. We generated ATIP-transgenic (Tg) mice, and cultured vascular smooth muscle cells (VSMCs). Persistent angiotensin II stimulation induced increases in SA-β-gal-positive cells and the level of a DNA damage marker, 8-OHdG in VSMC, whereas these effects of angiotensin II were attenuated in VSMC prepared from ATIP-Tg mice...
May 2012: Journal of the American Society of Hypertension: JASH
Derek T Warren, Catherine M Shanahan
Accumulation of DNA damage is a major driving force of normal cellular aging and has recently been demonstrated to hasten the development of vascular diseases such as atherosclerosis. VSMCs (vascular smooth muscle cells) are essential for vessel wall integrity and repair, and maintenance of their proliferative capacity is essential for vascular health. The signalling pathways that determine VSMC aging remain poorly defined; however, recent evidence implicates persistent DNA damage and the A-type nuclear lamins as key regulators of this process...
December 2011: Biochemical Society Transactions
Fabiola Olivieri, Ilaria Mazzanti, Angela M Abbatecola, Rina Recchioni, Fiorella Marcheselli, Antonio D Procopio, Roberto Antonicelli
Statins are well established drugs for primary and secondary prevention of coronary artery disease (CAD). Despite the well-known ability of statins to lower cholesterol, it is now clear that clinical benefits are also substantially higher than expected and several clinical trials, like JUPITER (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin trial) have indicated that such clinical effects are independent of cholesterol reduction. These cholesterol-independent actions have been named "pleiotropic effects" and include: anti-oxidation and anti-inflammatory effects, modulation of immune activation, stabilization of atherosclerotic plaque, decreased platelet activation, inhibition of cardiac hypertrophy, reduction of cytokine-mediated vascular smooth muscle cell (VSMC) proliferation and improvement of endothelial function...
March 2012: Current Vascular Pharmacology
Hyo Jung Kim, Sun Ah Ham, Kyung Shin Paek, Jung Seok Hwang, Si Young Jung, Min Young Kim, Hanna Jin, Eun Sil Kang, Im Sun Woo, Hye Jung Kim, Jae Heun Lee, Ki Churl Chang, Chang Woo Han, Han Geuk Seo
This study evaluated peroxisome proliferator-activated receptor (PPAR) δ as a potential target for therapeutic intervention in Ang II-induced senescence in human vascular smooth muscle cells (hVSMCs). Activation of PPARδ by GW501516, a specific agonist of PPARδ, significantly inhibited the Ang II-induced premature senescence of hVSMCs. Agonist-activated PPARδ suppressed the generation of Ang II-triggered reactive oxygen species (ROS) with a concomitant reduction in DNA damage. Notably, GW501516 up-regulated the expression of antioxidant genes, such as glutathione peroxidase 1, thioredoxin 1, manganese superoxide dismutase and heme oxygenase 1...
March 25, 2011: Biochemical and Biophysical Research Communications
Liang Zhang, Congli Zhu, Xiaofang Zhang, Yu Wan, Jian Song
OBJECTIVE: To investigate the mechanism for the dual effects of estrogen on vascular smooth muscle cells (VSMCs). METHODS: Cultured rat VSMCs were exposed to gradient concentrations (10(-9)-10(-5)M) of 17β-estradiol (E(2)) with or without pre-administration of a broad-spectrum CYP450 inhibitor 1-aminobenzotriazole (ABT) (10×10(-6)M) and an estrogen receptor (ER) antagonist ICI 182,780 (10(-6)M), respectively. The growth, cell cycle progression, premature senescence, estrogen metabolites, reactive oxygen species (ROS) and DNA damage of the cells were analyzed with cell counting assay, flow cytometry, Western blot, liquid chromatography-mass spectrometry and comet assay, respectively...
February 2011: Steroids
Cassandra D Ragnauth, Derek T Warren, Yiwen Liu, Rosamund McNair, Tamara Tajsic, Nichola Figg, Rukshana Shroff, Jeremy Skepper, Catherine M Shanahan
BACKGROUND: Hutchinson-Gilford progeria syndrome is a rare inherited disorder of premature aging caused by mutations in LMNA or Zmpste24 that disrupt nuclear lamin A processing, leading to the accumulation of prelamin A. Patients develop severe premature arteriosclerosis characterized by vascular smooth muscle cell (VSMC) calcification and attrition. METHODS AND RESULTS: To determine whether defective lamin A processing is associated with vascular aging in the normal population, we examined the profile of lamin A expression in normal and aged VSMCs...
May 25, 2010: Circulation
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