Multiple functions of autophagy in vascular calcification

Abstract

Background Vascular calcification is a closely linked to cardiovascular diseases, such as atherosclerosis, chronic kidney disease, diabetes, hypertension and aging. The extent of vascular calcification is closely correlate with adverse clinical events and cardiovascular all-cause mortality. The role of autophagy in vascular calcification is complex with many mechanistic unknowns. Methods In this review, we analyze the current known mechanisms of autophagy in vascular calcification and discuss the theoretical advantages of targeting autophagy as an intervention against vascular calcification. Results Here we summarize the functional link between vascular calcification and autophagy in both animal models of and human cardiovascular disease. Firstly, autophagy can reduce calcification by inhibiting the osteogenic differentiation of VSMCs related to ANCR, ERα, β-catenin, HIF-1a/PDK4, p62, miR-30b, BECN1, mTOR, SOX9, GHSR/ERK, and AMPK signaling. Conversely, autophagy can induce osteoblast differentiation and calcification as mediated by CREB, degradation of elastin, and lncRNA H19 and DUSP5 mediated ERK signaling. Secondly, autophagy also links apoptosis and vascular calcification through AMPK/mTOR/ULK1, Wnt/β-catenin and GAS6/AXL synthesis, as apoptotic cells become the nidus for calcium-phosphate crystal deposition. The failure of mitophagy can activate Drp1, BNIP3, and NR4A1/DNA‑PKcs/p53 mediated intrinsic apoptotic pathways, which have been closely linked to the formation of vascular calcification. Additionally, autophagy also plays a role in osteogenesis by regulating vascular calcification, which in turn regulates expression of proteins related to bone development, such as osteocalcin, osteonectin, etc. and regulated by mTOR, EphrinB2 and RhoA. Furthermore, autophagy also promotes vitamin K2-induced MC3T3 E1 osteoblast differentiation and FGFR4/FGF18- and JNK/complex VPS34–beclin-1-related bone mineralization via vascular calcification. Conclusion The interaction between autophagy and vascular calcification are complicated, with their interaction affected by the disease process, anatomical location, and the surrounding microenvironment. Autophagy activation in existent cellular damage is considered protective, while defective autophagy in normal cells result in apoptotic activation. Identifying and maintaining cells at the delicate line between these two states may hold the key to reducing vascular calcification, in which autophagy associated clinical strategy could be developed.

Galectin-3 induces vascular smooth muscle cells calcification via AMPK/TXNIP pathway

“…In atherosclerotic plaque, there is an increase expression of autophagy related proteins [ 21 ]. In order to explore the possible mechanisms of how TXNIP mediated galectin-3-induced VSMCs osteogenic differentiation, we focus on the autophagy process.…”

Recent advances of the mammalian target of rapamycin signaling in mesenchymal stem cells

“…According to a recent study, inhibition of the PI3K-Akt-mTOR pathway promotes osteogenic/dentine differentiation in SCAPs in vitro and in vivo ( Tanaka et al, 2018 ). Recent studies have shown that osteoblasts derived from vascular smooth muscle cells (VSMCs) and MSCs are modulated by autophagy to promote the transformation of calcification signals in vascular structures ( Shanahan, 2013 ; Lee et al, 2014 ; Caffarelli et al, 2017 ; Zhou et al, 2021 ). With the involvement of autophagic proteins, AMPK activation powerfully links Akt/mTOR-associated autophagy to the osteogenic differentiation of MSCs ( Zhou et al, 2021 ).…”

“…Recent studies have shown that osteoblasts derived from vascular smooth muscle cells (VSMCs) and MSCs are modulated by autophagy to promote the transformation of calcification signals in vascular structures ( Shanahan, 2013 ; Lee et al, 2014 ; Caffarelli et al, 2017 ; Zhou et al, 2021 ). With the involvement of autophagic proteins, AMPK activation powerfully links Akt/mTOR-associated autophagy to the osteogenic differentiation of MSCs ( Zhou et al, 2021 ). MiR-100-5p and miR-143-3p are involved in regulating the mTOR signaling pathway and promoting osteogenesis ( Cen et al, 2021 ).…”

The two facets of receptor tyrosine kinase in cardiovascular calcification—can tyrosine kinase inhibitors benefit cardiovascular system?

“…Other novel drivers for VC are autophagy and mitochondrial dysfunction. Autophagy has multiple functions in VC, as reviewed elsewhere ( 9 ). It affects VC by interfering with osteogenic differentiation of VSMCs, inhibition of apoptosis, and regulation of MV release.…”