Human electronegative LDL induces mitochondrial dysfunction and premature senescence of vascular cells in vivo

Yu Chen Wang, An Sheng Lee, Long Sheng Lu, Liang Yin Ke, Wei Yu Chen, Jian Wen Dong, Jonathan Lu, Zhenping Chen, Chih Sheng Chu, Hua Chen Chan, Taha Y. Kuzan, Ming Hsien Tsai, Wen Li Hsu, Richard A.F. Dixon, Tatsuya Sawamura, Kuan Cheng Chang, Chu Huang Chen

Research output: Contribution to journalArticle

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Abstract

Dysregulation of plasma lipids is associated with age-related cardiovascular diseases. L5, the most electronegative subfraction of chromatographically resolved low-density lipoprotein (LDL), induces endothelial dysfunction, whereas the least electronegative subfraction, L1, does not. In this study, we examined the effects of L5 on endothelial senescence and its underlying mechanisms. C57B6/J mice were intravenously injected with L5 or L1 (2 mg kg−1 day−1) from human plasma. After 4 weeks, nuclear γH2AX deposition and senescence-associated β-galactosidase staining indicative of DNA damage and premature senescence, respectively, were increased in the aortic endothelium of L5-treated but not L1-treated mice. Similar to that, in Syrian hamsters with elevated serum L5 levels induced by a high-fat diet, nuclear γH2AX deposition and senescence-associated β-galactosidase staining were increased in the aortic endothelium. This phenomenon was blocked in the presence of N-acetyl-cysteine (free-radical scavenger) or caffeine (ATM blocker), as well as in lectin-like oxidized LDL receptor-1 (LOX-1) knockout mice. In cultured human aortic endothelial cells, L5 augmented mitochondrial oxygen consumption and mitochondrial free-radical production, which led to ATM activation, nuclear γH2AX deposition, Chk2 phosphorylation, and TP53 stabilization. L5 also decreased human telomerase reverse transcriptase (hTERT) protein levels and activity. Pharmacologic or genetic manipulation of the reactive oxygen species (ROS)/ATM/Chk2/TP53 pathway efficiently blocked L5-induced endothelial senescence. In conclusion, L5 may promote mitochondrial free-radical production and activate the DNA damage response to induce premature vascular endothelial senescence that leads to atherosclerosis. Novel therapeutic strategies that target L5-induced endothelial senescence may be used to prevent and treat atherosclerotic vascular disease.

Original languageEnglish
Article numbere12792
JournalAging Cell
Volume17
Issue number4
DOIs
Publication statusPublished - Aug 1 2018

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Cell Aging
Blood Vessels
Galactosidases
DNA Damage
Free Radicals
Endothelium
Class E Scavenger Receptors
Staining and Labeling
Free Radical Scavengers
Mesocricetus
High Fat Diet
oxidized low density lipoprotein
Caffeine
Vascular Diseases
LDL Lipoproteins
Knockout Mice
Oxygen Consumption
Cysteine
Reactive Oxygen Species
Atherosclerosis

Keywords

  • atherosclerosis
  • DNA damage response
  • electronegative lipoproteins
  • mitochondria
  • premature senescence
  • telomerase

ASJC Scopus subject areas

  • Ageing
  • Cell Biology

Cite this

Human electronegative LDL induces mitochondrial dysfunction and premature senescence of vascular cells in vivo. / Wang, Yu Chen; Lee, An Sheng; Lu, Long Sheng; Ke, Liang Yin; Chen, Wei Yu; Dong, Jian Wen; Lu, Jonathan; Chen, Zhenping; Chu, Chih Sheng; Chan, Hua Chen; Kuzan, Taha Y.; Tsai, Ming Hsien; Hsu, Wen Li; Dixon, Richard A.F.; Sawamura, Tatsuya; Chang, Kuan Cheng; Chen, Chu Huang.

In: Aging Cell, Vol. 17, No. 4, e12792, 01.08.2018.

Research output: Contribution to journalArticle

Wang, YC, Lee, AS, Lu, LS, Ke, LY, Chen, WY, Dong, JW, Lu, J, Chen, Z, Chu, CS, Chan, HC, Kuzan, TY, Tsai, MH, Hsu, WL, Dixon, RAF, Sawamura, T, Chang, KC & Chen, CH 2018, 'Human electronegative LDL induces mitochondrial dysfunction and premature senescence of vascular cells in vivo', Aging Cell, vol. 17, no. 4, e12792. https://doi.org/10.1111/acel.12792
Wang, Yu Chen ; Lee, An Sheng ; Lu, Long Sheng ; Ke, Liang Yin ; Chen, Wei Yu ; Dong, Jian Wen ; Lu, Jonathan ; Chen, Zhenping ; Chu, Chih Sheng ; Chan, Hua Chen ; Kuzan, Taha Y. ; Tsai, Ming Hsien ; Hsu, Wen Li ; Dixon, Richard A.F. ; Sawamura, Tatsuya ; Chang, Kuan Cheng ; Chen, Chu Huang. / Human electronegative LDL induces mitochondrial dysfunction and premature senescence of vascular cells in vivo. In: Aging Cell. 2018 ; Vol. 17, No. 4.
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abstract = "Dysregulation of plasma lipids is associated with age-related cardiovascular diseases. L5, the most electronegative subfraction of chromatographically resolved low-density lipoprotein (LDL), induces endothelial dysfunction, whereas the least electronegative subfraction, L1, does not. In this study, we examined the effects of L5 on endothelial senescence and its underlying mechanisms. C57B6/J mice were intravenously injected with L5 or L1 (2 mg kg−1 day−1) from human plasma. After 4 weeks, nuclear γH2AX deposition and senescence-associated β-galactosidase staining indicative of DNA damage and premature senescence, respectively, were increased in the aortic endothelium of L5-treated but not L1-treated mice. Similar to that, in Syrian hamsters with elevated serum L5 levels induced by a high-fat diet, nuclear γH2AX deposition and senescence-associated β-galactosidase staining were increased in the aortic endothelium. This phenomenon was blocked in the presence of N-acetyl-cysteine (free-radical scavenger) or caffeine (ATM blocker), as well as in lectin-like oxidized LDL receptor-1 (LOX-1) knockout mice. In cultured human aortic endothelial cells, L5 augmented mitochondrial oxygen consumption and mitochondrial free-radical production, which led to ATM activation, nuclear γH2AX deposition, Chk2 phosphorylation, and TP53 stabilization. L5 also decreased human telomerase reverse transcriptase (hTERT) protein levels and activity. Pharmacologic or genetic manipulation of the reactive oxygen species (ROS)/ATM/Chk2/TP53 pathway efficiently blocked L5-induced endothelial senescence. In conclusion, L5 may promote mitochondrial free-radical production and activate the DNA damage response to induce premature vascular endothelial senescence that leads to atherosclerosis. Novel therapeutic strategies that target L5-induced endothelial senescence may be used to prevent and treat atherosclerotic vascular disease.",
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AU - Lee, An Sheng

AU - Lu, Long Sheng

AU - Ke, Liang Yin

AU - Chen, Wei Yu

AU - Dong, Jian Wen

AU - Lu, Jonathan

AU - Chen, Zhenping

AU - Chu, Chih Sheng

AU - Chan, Hua Chen

AU - Kuzan, Taha Y.

AU - Tsai, Ming Hsien

AU - Hsu, Wen Li

AU - Dixon, Richard A.F.

AU - Sawamura, Tatsuya

AU - Chang, Kuan Cheng

AU - Chen, Chu Huang

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