SET8, a novel regulator to ameliorate vascular calcification via activating PI3K/Akt mediated anti-apoptotic effects

Abstract

Previous studies have showed that the apoptosis of vascular smooth muscle cells (VSMCs) underlies the mechanism of pathological calcifications in patients with chronic kidney disease (CKD). SET domain-containing protein 8 (SET8), as an efficient protein has been reported to modulate cell apoptosis in hepatocellular carcinoma cell, esophageal squamous cell and neuronal cell through regulating pathological processes, such as cell-cycle progression and transcription regulation. However, whether SET8 is involved in high phosphorus induced vascular calcification by mediating apoptosis remains undefined. Here, we reported that SET8 was located both in nucleus and cytoplasm, and significantly downregulated in calcification models. SET8 deficiency promoted the apoptosis of VSMCs, which was indicated by the increased Bax/Bcl-2 and cleaved caspase-3/total caspase-3 ratios. Mechanistically, PI3K/Akt pathway was mediated by SET8 and inhibition of PI3K/Akt signaling pathway by giving LY294002 or transfecting Akt phosphorylation inactivated mutation plasmid increased apoptosis and calcification. Akt phosphorylation constitutively activated mutation could reduce apoptosis and calcification of VSMCs. Furthermore, exogenous overexpression of SET8 could reverse the effect of PI3K/Akt inhibition on the apoptosis and calcification of VSMCs. In summary, our researches suggested that SET8 overexpression ameliorated high phosphorus induced calcification of vascular smooth muscle cells via activating PI3K/Akt mediated anti-apoptotic effects.

KAP1 modulates osteogenic differentiation via the ERK/Runx2 cascade in vascular smooth muscle cells

“…After acclimatization, rats were randomly divided into two groups (n = 10): namely control group and VC group. Rat model of VC was constructed by 5/6 nephrectomy combined with a high phosphate diet protocol as previously described [33]. Brie y, rst, rats were anesthetized and underwent a 2/3 left nephrectomy.…”

“…Isolation of VSMCs was performed from the aortas of Sprague-Dawley rats (8-weeks old) with the use of the explant method as described in a previous study [33]. After cultured in Dulbecco's Modi ed Eagle Medium containing 10% fetal bovine serum, cells were incubated at 37° C in humidi ed 5% CO2.…”

Possible effects of fibroblast growth factor 21 on vascular calcification via suppressing activating transcription factor 4 mediated apoptosis and osteogenic transformation in rats

“…Furthermore, recent evidence indicated that apoptosis is a significant process in the onset of VC, which is usually observed before the formation of calcified nodules in VSMCs 20 . Apoptotic bodies derived from VSMCs might act as nucleating structures for calcium‐phosphate crystals deposited in the vascular wall, finally activating the procedure of VC 21 .…”

“…Furthermore, recent evidence indicated that apoptosis is a significant process in the onset of VC, which is usually observed before the formation of calcified nodules in VSMCs. 20 Apoptotic bodies derived from VSMCs might act as nucleating structures for calcium-phosphate crystals deposited in the vascular wall, finally activating the procedure of VC. 21 Moreover, ERS was proved to be one of the upstream of apoptosis in various pathogenesis, such as diabetes mellitus, atherosclerosis, 22 and chronic kidney disease, 23 all of which are associated with VC in the clinic.…”

Histone Lysine Methylation Modification and Its Role in Vascular Calcification

“…Although SET8 has a complex mechanism of action in H4K20 and non-histone catalysis, in terms of overall effect SET8 is significantly downregulated in the calcification model ( 114 ). The methylation modification of H4K20 is highly complex due to the different effects at different levels of methylation; therefore, researchers may focus on the specific role of SET8 in different pathways and the effects of other H4K20 methyltransferases on VC.…”