Intermedin1-53 attenuates aging-associated vascular calcification in rats by upregulating sirtuin 1

Abstract

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 VDNtreated 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.

The Protective Effects of the Autophagic and Lysosomal Machinery in Vascular and Valvular Calcification: A Systematic Review

“…In line with these findings, metformin ameliorated VSMC calcification in vitro through AMPK activation [ 59 ]. Additionally, both the peptide ghrelin and the protein intermedin 1-53 (IM 1-53 ) attenuated VCN through AMPK activation both, in vivo and in vitro [ 60 , 61 ]. Ghrelin induced both LC3-II and Beclin1 while IM 1-53 upregulated Sirt1 expression.…”

“…Interestingly, intermedin 1-53 (IM 1-53 ) also ameliorated VCN while the authors additionally observed a marked increase in Klotho expression after IM 1-53 treatment. This increase in Klotho expression by IM 1-53 , is possibly the consequence of AMPK-dependent inhibition of mTOR [ 60 ]. Indeed, there are multiple lines of evidence supporting AMPK as an anti-VSMC calcification mechanism.…”

“…Indeed, there are multiple lines of evidence supporting AMPK as an anti-VSMC calcification mechanism. Melatonin, metformin, ghrelin, intermedin 1-53 and MOTS-c have all been demonstrated to ameliorate VCN in vitro and/or in vivo, accredited due to their ability to increase AMPK activity [ 58 , 59 , 60 , 61 , 62 ].…”

“…after IM1-53 treatment. This increase in Klotho expression by IM1-53, is possibly the consequence of AMPK-dependent inhibition of mTOR [60]. Indeed, there are multiple lines of evidence supporting AMPK as an anti-VSMC calcification mechanism.…”

Uncarboxylated osteocalcin promotes osteogenesis and inhibits adipogenesis of mouse bone marrow‑derived mesenchymal stem cells via the PKA‑AMPK‑SIRT1 axis

“…unOC can upregulate the expression levels of p-PKA, p-AMPK and SIRT1. As PKA and AMPK regulate SIRT1 in cell differentiation (37,38), the PKA-AMPK pathway was examined to find if it was required for unOC to promote osteogenic differentiation in BMSCs. The PKA inhibitor, H89, was used to detect the signaling pathway through which unOC regulated the differentiation of mouse BMSCs.…”