Neuregulin-1 attenuates stress-induced vascular senescence. Issue 7 (8th March 2018)

• Record Type: Journal Article
• Authors: Shakeri, Hadis; Gevaert, Andreas B; Schrijvers, Dorien M; De Meyer, Guido R Y; De Keulenaer, Gilles W; Guns, Pieter-Jan D F; Lemmens, Katrien; Segers, Vincent F
• Is Part Of: Cardiovascular research. Volume 114:Issue 7(2018)
• Page Start: 1041
• Page End: 1051
• Publication Date: 2018-03-08
• Subjects: Neuregulin-1 -- Cellular senescence -- Cardiovascular diseases -- Diabetes; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvy059
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: 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 µM hydrogen peroxide (H2 O2 ). Cellular senescence was confirmed after 72 h using senescence-associated-β-galactosidase staining (SA-β-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 H2 O2 -induced senescence, as shown by a lower number of SA-β-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 (ErbB4 f/+ SM22α-Cre+) showed earlier cellular senescence in vitro compared with wild-type (ErbB4 +/+ SM22α-Cre+) SMCs. Furthermore, when rendered diabetic with STZ, ErbB4 f/+ SM22α-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 .