| First Author | Shakeri H | Year | 2018 |
| Journal | Cardiovasc Res | Volume | 114 |
| Issue | 7 | Pages | 1041-1051 |
| PubMed ID | 29528383 | Mgi Jnum | J:330118 |
| Mgi Id | MGI:6878719 | Doi | 10.1093/cvr/cvy059 |
| Citation | Shakeri H, et al. (2018) Neuregulin-1 attenuates stress-induced vascular senescence. Cardiovasc Res 114(7):1041-1051 |
| abstractText | 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 microM 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-beta-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 (ErbB4f/+ SM22alpha-Cre+) showed earlier cellular senescence in vitro compared with wild-type (ErbB4+/+ SM22alpha-Cre+) SMCs. Furthermore, when rendered diabetic with STZ, ErbB4f/+ SM22alpha-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. |
