Research Paper Volume 12, Issue 7 pp 5651—5674
Intermedin1-53 attenuates aging-associated vascular calcification in rats by upregulating sirtuin 1
- 1 Laboratory of Cardiovascular Bioactive Molecule, School of Basic Medical Sciences, Peking University, Beijing 100083, China
- 2 Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, Beijing 100083, China
- 3 Department of Pathogen Biology, School of Basic Medical Sciences, Peking University, Beijing 100083, China
- 4 Department of Gynaecology and Obstetrics, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
- 5 Shanghai University of Medicine and Health Sciences, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China
- 6 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100083, China
Received: September 6, 2019 Accepted: January 27, 2020 Published: March 31, 2020https://doi.org/10.18632/aging.102934
How to Cite
Copyright © 2020 Chen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Vascular calcification is a common phenomenon in older adults. Intermedin (IMD) is a cardiovascular bioactive peptide inhibiting vascular calcification. In this study, we aimed to investigate whether IMD1-53 attenuates aging-associated vascular calcification. Vascular calcification was induced by vitamin D3 plus nicotine (VDN) in young and old rats. The calcification in aortas was more severe in old rats treated with VDN than young control rats, and IMD expression was lower. Exogenous administration of IMD1-53 significantly inhibited the calcium deposition in aortas and the osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) in VDN-treated old rats. Moreover, levels of aging-related p16, p21 and β-galactosidase were all greatly decreased by IMD1-53. These results were further confirmed in rat and human VSMCs in vitro. In addition, IMD-deficient mouse VSMCs showed senescence features coinciding with osteogenic transition as compared with wild-type mouse VSMCs. Mechanistically, IMD1-53 significantly increased the expression of the anti-aging factor sirtuin 1 (sirt1); the inhibitory effects of IMD1-53 on calcification and senescence were blocked by sirt1 knockdown. Furthermore, preincubation with inhibitors of PI3K, AMPK or PKA efficiently blunted the upregulatory effect of IMD1-53 on sirt1. Consequently, IMD1-53 could attenuate aging-associated vascular calcification by upregulating sirt1 via activating PI3K/Akt, AMPK and cAMP/PKA signaling.
IMD: Intermedin; VDN: vitamin D3 plus nicotine; VSMC: vascular smooth muscle cell; sirt1: sirtuin 1; acetyl-p53: acetylated p53; SM-22α: smooth muscle-22 alpha; α-SMA: alpha-smooth muscle actin; RUNX2: runt-related transcription factor 2; BMP2: bone morphogenetic protein 2; ALP: alkaline phosphatase; CRLR: calcitonin receptor-like receptor; RAMP: receptor activity modifying protein; SA-β-gal: senescence-associated β-galactosidase; WT: wild type; IMDSMC-/-: VSMC-specific IMD-deficient; klotho+/-: heterozygous klotho-deficient; PI3K/Akt: phosphoinositide 3-kinase/protein kinase B; cAMP/PKA: cyclic adenosine monophosphate/protein kinase A; AMPK: AMP-activated protein kinase.