Endogenous TGF-β Activity Is Modified during Cellular Aging: Effects on Metalloproteinase and TIMP-1 Expression

Zeng, Gu-Qing; McCue, Heather M.; Mastrangelo, Laura; Millis, Albert J.T.

doi:10.1006/excr.1996.0326

Cited by 87 publications

(49 citation statements)

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“…Senescent cells may also promote plaque instability by overexpressing proteins such as adhesion molecules, 47 regulators of hemostasis, 48 and matrix metalloproteinases. 49 In conclusion, we demonstrate that human atherosclerosis is characterized by VSMC senescence and marked telomere shortening and that telomerase expression can delay senescence. Oxidative DNA damage is seen in vivo, and chronic oxidative stress accelerates telomere loss and VSMC senescence.…”

Section: Circulation Research July 21 2006mentioning

confidence: 58%

Vascular Smooth Muscle Cells Undergo Telomere-Based Senescence in Human Atherosclerosis

Matthews

Gorenne²,

Scott³

et al. 2006

Circulation Research

546

434

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Abstract-Although human atherosclerosis is associated with aging, direct evidence of cellular senescence and the mechanism of senescence in vascular smooth muscle cells (VSMCs) in atherosclerotic plaques is lacking. We examined normal vessels and plaques by histochemistry, Southern blotting, and fluorescence in situ hybridization for telomere signals. (VSMCs), and intracellular and extracellular lipids. Plaque disruption results in acute myocardial infarction and stroke, whereas repeated rounds of subclinical rupture and repair also promote plaque growth. Although VSMC proliferation occurs in atherogenesis, most proliferating cells are macrophages, and VSMC mitotic rates are lower in advanced plaques than early lesions, even after plaque rupture, 1 suggesting that plaque VSMCs may exhibit senescence.Cellular senescence can be defined as cell cycle arrest accompanying the exhaustion of replicative potential. 2 Senescent cells display a characteristic morphology (vacuolated, flattened cells) and gene expression, including markers such as senescence-associated ␤-galactosidase (SA␤G). 3 Senescence may be triggered by 2 broadly different mechanisms. In most primary cells, the telomeres of chromosomes shorten at each cell division because of incomplete chromosomal replication. Replicative senescence may be induced at critical telomere lengths or structures, such as telomeric fusion or dicentrics or loss of telomere-bound factors. 4,5 Cells also undergo "stress-induced premature senescence" (SIPS), for example, in response to activated oncogenes (eg, Ha-Ras) and suboptimal culture conditions. 6 Although telomere loss occurs with replication, both premature senescence and telomere breaks may be induced by oxidative DNA damage. Reactive oxygen species (ROS), particularly superoxide anions, hydrogen peroxide, and hydroxyl radicals, can produce a large variety of DNA damage, including DNA strand breaks and DNA base modifications. ROS can accelerate telomere loss during replication in some cell types 7 but also induces premature senescence independently of telomere shortening. 8 Increased levels of ROS are Original

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Section: Circulation Research July 21 2006mentioning

confidence: 58%

Vascular Smooth Muscle Cells Undergo Telomere-Based Senescence in Human Atherosclerosis

Matthews

Gorenne²,

Scott³

et al. 2006

Circulation Research

546

434

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“…The third is TGF-β. The level of active TGF-β1 is decreased during replicative senescence, and XIAP gene expression and function is positively regulated by exposure to TGF-β (Zeng et al 1996;Van Themsche et al 2010). However, these hypotheses have not been tested in this paper and will be investigated in future studies.…”

Section: Discussionmentioning

confidence: 95%

Variations in the protein level of Omi/HtrA2 in the heart of aged rats may contribute to the increased susceptibility of cardiomyocytes to ischemia/reperfusion injury and cell death

Wang

Zhang

Liu

et al. 2012

AGE

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Survival after acute myocardial infarction is decreased in elderly patients. The enhanced rates of apoptosis in the aging heart exacerbate myocardial ischemia/reperfusion (MI/R) injury. We have recently demonstrated that the X-linked inhibitor of apoptosis protein (XIAP), the most potent endogenous inhibitor of apoptosis, was decreased in aging rats' hearts. XIAP was balanced by two mitochondria proteins, Omi/HtrA2 and Smac/DIABLO. However, the implicative role of XIAP, Omi/HtrA2, and Smac/DIABLO to aging-related MI/R injury has not been previously investigated. In our study, male aging rats (20-24 months) or young adult rats (4-6 months) were subjected to 30 min of myocardial ischemia followed by reperfusion. MI/R-induced cardiac injury was enhanced in aging rats, as evidenced by aggravated cardiac dysfunction, enlarged infarct size, and increased myocardial apoptosis (TUNEL and caspase-3 activity). Then, the XIAP, Omi/HtrA2, and Smac/ DIABLO protein and mRNA expression was detected. XIAP protein and mRNA expression was decreased in both aging hearts and aging hearts subjected to MI/R. Meanwhile, myocardial XIAP protein expression was correlated to cardiac function after MI/R. However, Omi/HtrA2, but not Smac/DIABLO, expression was increased in aging hearts. Moreover, the translocation of Omi/HtrA2 from mitochondria to cytosol was increased in both aging hearts and aging hearts subjected to MI/R. Treatment with ucf-101 (a novel and specific Omi/HtrA2 inhibitor) attenuated XIAP degradation and caspase-3 activity and exerted cardioprotective effects. Taken together, these results demonstrated that increased expression and leakage of Omi/HtrA2 enhanced MI/R injury in aging hearts via degrading XIAP and promoting myocardial apoptosis.

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“…22 Telomere shortening in key vascular cells, in turn, and the related phenomena of cellular aging and replicative cell senescence have been reported to evoke multiple proatherogenic consequences, 1 such as impairment of endothelial repair and vessel remodeling, unfavorable changes in gene expression and cell phenotype, upregulation of immunoattractants (intercellular adhesion molecule-1 23 and vascular cell adhesion molecule-1 24 ) and prothrombotic molecules (plasminogen activator inhibitor-1 8 ), and matrix degeneration 25 with critical destabilization of plaques. In stable atherosclerosis, senescent cells are few, whereas in advanced complicated lesions, senescent cells accumulate as the result of high cell turnover, prominent oxidative and inflammatory stress, and impaired phagocytic clearance.…”

Section: Discussionmentioning

confidence: 99%

Cellular Aging Reflected by Leukocyte Telomere Length Predicts Advanced Atherosclerosis and Cardiovascular Disease Risk

Willeit

Willeit²,

Brandstätter³

et al. 2010

ATVB

268

198

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Objective-To determine the association between leukocyte telomere length (TL) and atherosclerosis and its clinical sequelae stroke and myocardial infarction. Methods and Results-Within the scope of the prospective population-based Bruneck Study, leukocyte TL was measured by quantitative polymerase chain reaction in 800 women and men aged 45 to 84 years (in 1995). The manifestation of cardiovascular disease (CVD) (1995)(1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005) and the progression of atherosclerosis (1995)(1996)(1997)(1998)(1999)(2000) were carefully assessed. In multivariable Cox models, baseline TL emerged as a significant and independent risk predictor for the composite CVD end point and its individual components (myocardial infarction and stroke); however, this was not the case for de novo stable angina and intermittent claudication. Subjects in the top and bottom TL tertile group differed in their CVD risk by a factor of 2.72 (95% CI, 1.41 to 5.28), which is the risk ratio attributable to a 13.9-year difference in chronological age. Remarkably, in our atherosclerosis progression model, TL was strongly associated with advanced, but not early, atherogenesis. All findings were consistent in women and men. Conclusion-Our findings indicate a differential role of telomere shortening in the various stages of atherosclerosis, with preferential involvement in advanced vessel pathology and acute vascular syndromes. (Arterioscler Thromb Vasc Biol.

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Endogenous TGF-β Activity Is Modified during Cellular Aging: Effects on Metalloproteinase and TIMP-1 Expression

Cited by 87 publications

References 0 publications

Vascular Smooth Muscle Cells Undergo Telomere-Based Senescence in Human Atherosclerosis

Vascular Smooth Muscle Cells Undergo Telomere-Based Senescence in Human Atherosclerosis

Variations in the protein level of Omi/HtrA2 in the heart of aged rats may contribute to the increased susceptibility of cardiomyocytes to ischemia/reperfusion injury and cell death

Cellular Aging Reflected by Leukocyte Telomere Length Predicts Advanced Atherosclerosis and Cardiovascular Disease Risk

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