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Title
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Neuregulin-1 attenuates stress-induced vascular senescence
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Author
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Abstract
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| Aims Cardiovascular ageing is a key determinant of life expectancy. Cellular senescence, a state of irreversible cell cycle arrest, is an important contributor to ageing due to the accumulation of damaged cells. Targeting cellular senescence could prevent age-related cardiovascular diseases. In this study, we investigated the effects of neuregulin-1 (NRG-1), an epidermal growth factor with cardioprotective and anti-atherosclerotic effects, on cellular senescence. Methods and results Senescence was induced in cultured rat aortic endothelial cells (ECs) and aortic smooth muscle cells (SMCs) by 2 h exposure to 30 mu M hydrogen peroxide (H2O2). Cellular senescence was confirmed after 72 h using senescence-associated-beta-galactosidase staining (SA-beta-gal), cell surface area, and western blot analyses of SA pathways (acetyl-p53, p21). Recombinant human NRG-1 (rhNRG-1, 20 ng/mL) significantly reduced H2O2-induced senescence, as shown by a lower number of SA-b-gal positive cells, smaller surface area and lower expression of acetyl-p53. In C57BL/6 male mice rendered diabetic with streptozotocin (STZ), rhNRG-1 attenuated cellular senescence in aortic ECs and SMCs. Next, we created mice with SMC-specific knockdown of the NRG-1 receptor ErbB4. Aortic SMCs isolated from SMC-specific ErbB4 deficient mice (rbB4(f/+) SM22 alpha-Cre+) showed earlier cellular senescence in vitro compared with wild-type (ErbB4(+/+) SM22 alpha-Cre+) SMCs. Furthermore, when rendered diabetic with STZ, ErbB4(f/+) SM22 alpha-Cre+ male mice showed significantly more vascular senescence than their diabetic wild-type littermates and had increased mortality. Conclusions This study is the first to explore the role of NRG-1 in vascular senescence. Our data demonstrate that NRG-1 markedly inhibits stress-induced premature senescence in vascular cells in vitro and in the aorta of diabetic mice in vivo. Consistently, deficiency in the NRG-1 receptor ErbB4 provokes cellular senescence in vitro as well as in vivo. |
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Language
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English
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Source (journal)
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Cardiovascular research / European Society of Cardiology [Biot] - London
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Publication
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London
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2018
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ISSN
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0008-6363
[print]
1755-3245
[online]
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DOI
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10.1093/CVR/CVY059
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Volume/pages
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114
:7
(2018)
, p. 1041-1051
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ISI
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000434122000018
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Pubmed ID
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29528383
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Full text (Publisher's DOI)
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Full text (open access)
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Full text (publisher's version - intranet only)
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