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. 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. 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. 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.

中文翻译：

---

自噬在血管钙化中的多种功能

血管钙化与心血管疾病密切相关，如动脉粥样硬化、慢性肾病、糖尿病、高血压和衰老等。血管钙化的程度与不良临床事件和心血管全因死亡率密切相关。自噬在血管钙化中的作用是复杂的，有许多机制未知。在这篇综述中，我们分析了目前已知的血管钙化自噬机制，并讨论了靶向自噬作为干预血管钙化的理论优势。在这里，我们总结了人类心血管疾病和人类心血管疾病动物模型中血管钙化和自噬之间的功能联系。首先，自噬可以通过抑制与 ANCR、ERα、β-catenin、HIF-1a/PDK4、p62、miR-30b、BECN1、mTOR、SOX9、GHSR/ERK 和 AMPK 信号。相反，自噬可诱导成骨细胞分化和钙化，由 CREB、弹性蛋白降解以及 lncRNA H19 和 DUSP5 介导的 ERK 信号传导。其次，自噬还通过 AMPK/mTOR/ULK1、Wnt/β-catenin 和 GAS6/AXL 合成将细胞凋亡和血管钙化联系起来，因为凋亡细胞成为磷酸钙晶体沉积的病灶。线粒体自噬的失败可以激活 Drp1、BNIP3 和 NR4A1/DNA-PKcs/p53 介导的内在凋亡通路，这些通路与血管钙化的形成密切相关。此外，自噬还通过调节血管钙化在成骨中起作用，血管钙化进而调节与骨发育相关的蛋白质的表达，如骨钙素、骨连接素等。并受 mTOR、EphrinB2 和 RhoA 的调控。此外，自噬还通过血管钙化促进维生素 K2 诱导的 MC3T3 E1 成骨细胞分化和 FGFR4/FGF18-和 JNK/复合 VPS34-beclin-1 相关的骨矿化。自噬与血管钙化之间的相互作用是复杂的，其相互作用受疾病过程、解剖位置和周围微环境的影响。现有细胞损伤中的自噬激活被认为是保护性的，而正常细胞中的自噬缺陷导致细胞凋亡激活。在这两种状态之间的微妙线上识别和维持细胞可能是减少血管钙化的关键，其中可以开发与自噬相关的临床策略。自噬还通过血管钙化促进维生素 K2 诱导的 MC3T3 E1 成骨细胞分化和 FGFR4/FGF18-和 JNK/复合 VPS34-beclin-1 相关的骨矿化。自噬与血管钙化之间的相互作用是复杂的，其相互作用受疾病过程、解剖位置和周围微环境的影响。现有细胞损伤中的自噬激活被认为是保护性的，而正常细胞中的自噬缺陷导致细胞凋亡激活。在这两种状态之间的微妙线上识别和维持细胞可能是减少血管钙化的关键，其中可以开发与自噬相关的临床策略。自噬还通过血管钙化促进维生素 K2 诱导的 MC3T3 E1 成骨细胞分化和 FGFR4/FGF18-和 JNK/复合 VPS34-beclin-1 相关的骨矿化。自噬与血管钙化之间的相互作用是复杂的，其相互作用受疾病过程、解剖位置和周围微环境的影响。现有细胞损伤中的自噬激活被认为是保护性的，而正常细胞中的自噬缺陷导致细胞凋亡激活。在这两种状态之间的微妙线上识别和维持细胞可能是减少血管钙化的关键，其中可以开发与自噬相关的临床策略。