切换至 "中华医学电子期刊资源库"

中华诊断学电子杂志 ›› 2025, Vol. 13 ›› Issue (03) : 171 -176. doi: 10.3877/cma.j.issn.2095-655X.2025.03.005

生物医学技术

线粒体功能障碍在动脉中层钙化中的机制及治疗研究进展
张昆1, 梁秋华2,()   
  1. 1272067 济宁医学院临床医学院
    2272029 济宁医学院附属医院内分泌遗传代谢科
  • 收稿日期:2025-08-08 出版日期:2025-08-26
  • 通信作者: 梁秋华
  • 基金资助:
    齐鲁卫生与健康领军人才工程(2021-QLJQ-001)

Research progress on the mechanism and treatment of mitochondrial dysfunction in arterial medial calcification

Kun Zhang1, Qiuhua Liang2,()   

  1. 1College of Clinical Medicine, Jining Medical University, Jining 272067, China
    2Department of Endocrinology, Genetics and Metabolism, the Affiliated Hospital of Jining Medical University, Jining 272029, China
  • Received:2025-08-08 Published:2025-08-26
  • Corresponding author: Qiuhua Liang
引用本文:

张昆, 梁秋华. 线粒体功能障碍在动脉中层钙化中的机制及治疗研究进展[J/OL]. 中华诊断学电子杂志, 2025, 13(03): 171-176.

Kun Zhang, Qiuhua Liang. Research progress on the mechanism and treatment of mitochondrial dysfunction in arterial medial calcification[J/OL]. Chinese Journal of Diagnostics(Electronic Edition), 2025, 13(03): 171-176.

动脉钙化是钙盐异常沉积于动脉壁的病理过程,可根据病变部位分为内层钙化和中层钙化;其中动脉中层钙化常见于慢性肾病、糖尿病及老年人群,与心血管疾病密切相关。近年来,线粒体功能障碍在该过程中的作用越来越受到关注。线粒体不仅为细胞提供能量,还参与调控氧化应激和细胞凋亡等过程,其功能紊乱可促进血管平滑肌细胞向成骨样表型转化,加速钙盐沉积。笔者主要对近年来线粒体功能障碍在动脉中层钙化发病机制中的基础与临床研究进展进行综述,以进一步为临床防治动脉钙化提供新的思路。

Arterial calcification is a pathological process in which calcium salts abnormally deposit in the arterial wall. It can be classified into intimal calcification and medial calcification based on the lesion location. Among them, arterial medial calcification is common in patients with chronic kidney disease, diabetes, and the elderly, and is strongly associated with cardiovascular diseases. In recent years, the role of mitochondrial dysfunction in this process has attracted increasing attention. Mitochondria not only provide energy for cells but also participate in regulating oxidative stress and apoptosis. Their dysfunction can promote the transformation of vascular smooth muscle cells into an osteoblast-like phenotype and accelerate calcium salt deposition. The author mainly reviews the basic and clinical research progress of mitochondrial dysfunction in the pathogenesis of arterial middle calcification in recent years, in order to further provide new ideas for clinical prevention and treatment of arterial calcification.

图1 线粒体功能障碍在动脉中层钙化中的作用机制示意图注:多种危险因素(如高磷、高糖、高胆固醇、高草酸、炎症因子及尼古丁等)可通过线粒体引发一系列病理反应,包括OXPHOS受损、乳酸堆积、线粒体裂变增加与自噬异常,伴随mPTP开放和细胞色素c释放,最终导致细胞凋亡。同时,过量ROS及Ca2+超载可激活多条下游信号通路(如PI3K/AKT、ERK/mTOR、p38/MAPK、NF-κB及Smad1/5/8等),促进转录因子Runx2及成骨相关基因BMP2、Msx2的表达,从而驱动VSMCs的成骨分化。OXPHOS为氧化磷酸化;mPTP为线粒体通透性转变孔;ROS为活性氧;PI3K/AKT为磷脂酰肌醇3-激酶/蛋白激酶B信号通路;ERK/mTOR胞外信号调节激酶/哺乳动物雷帕霉素靶蛋白通路;p38/MAPK为p38丝裂原活化蛋白激酶通路;NF-κB为核因子κB信号通路;Smad1/5/8为Smad1/5/8信号转导蛋白(TGF-β/BMP下游介导因子);ETC为电子传递链;mtROS为线粒体活性氧;Runx2为Runt相关转录因子2;BMP2为骨形态发生蛋白2;Msx2为肌肉分节同源基因2;PDK4为丙酮酸脱氢酶激酶4;VSMCs为血管平滑肌细胞。本图由作者使用Figdraw软件绘制
表1 多种靶向线粒体功能在动脉中层钙化中的治疗策略
[1]
Lee SJLee IKJeon JH.Vascular calcification-new insights into its mechanism[J].Int J Mol Sci202021(8):2685.DOI:10.3390/ijms21082685.
[2]
Lanzer PHannan FMLanzer JD,et al.Medial arterial calcification:JACC state-of-the-art review[J].J Am Coll Cardiol202178(11):1145-1165.DOI:10.1016/j.jacc.2021.06.049.
[3]
Li MZhu YJaiswal SK,et al.Mitochondria homeostasis and vascular medial calcification[J].Calcif Tissue Int2021109(2):113-120.DOI:10.1007/s00223-021-00828-1.
[4]
Tang HYChen AQZhang H,et al.Vascular smooth muscle cells phenotypic switching in cardiovascular diseases[J].Cells202211(24):4060.DOI:10.3390/cells11244060.
[5]
Annesley SJFisher PR.Mitochondria in health and disease [J].Cells20198(7):680.DOI:10.3390/cells8070680.
[6]
Li ALLian LChen XN,et al.The role of mitochondria in myocardial damage caused by energy metabolism disorders:from mechanisms to therapeutics[J].Free Radic Biol Med2023(208):236-251.DOI:10.1016/j.freeradbiomed.2023.08.009.
[7]
Jiang M, Wang L, Sheng H. Mitochondria in depression:the dysfunction of mitochondrial energy metabolism and quality control systems[J].CNS Neurosci Ther202430(2):e14576.DOI:10.1111/cns.14576.
[8]
Yang SLian G.ROS and diseases:role in metabolism and energy supply[J].Mol Cell Biochem2020467(1-2):1-12.DOI:10.1007/s11010-019-03667-9.
[9]
Bertero EMaack C.Calcium signaling and reactive oxygen species in mitochondria[J].Circ Res2018122(10):1460-1478.DOI:10.1161/CIRCRESAHA.118.310082.
[10]
Mittler R.ROS are good [J].Trends Plant Sci201722(1):11-19.DOI:10.1016/j.tplants.2016.08.002.
[11]
Chan DC.Mitochondrial dynamics and its involvement in disease[J].Annu Rev Pathol2020(15):235-259.DOI:10.1146/annurev-pathmechdis-012419-032711.
[12]
Chen W, Zhao H, Li Y. Mitochondrial dynamics in health and disease:mechanisms and potential targets[J].Signal Transduct Target Ther20238(1):333.DOI:10.1038/s41392-023-01547-9.
[13]
Quintana-Cabrera R, Scorrano L. Determinants and outcomes of mitochondrial dynamics [J].Mol Cell202383(6):857-876.DOI:10.1016/j.molcel.2023.02.012.
[14]
Lu YLi ZZhang S,et al.Cellular mitophagy:mechanism,roles in diseases and small molecule pharmacological regulation[J].Theranostics202313(2):736-766.DOI:10.7150/thno.79876.
[15]
Onishi MYamano KSato M,et al.Molecular mechanisms and physiological functions of mitophagy [J].Embo J202140(3):e104705.DOI:10.15252/embj.2020104705.
[16]
Byon CHJaved ADai Q,et al.Oxidative stress induces vascular calcification through modulation of the osteogenic transcription factor Runx2 by AKT signaling[J].J Biol Chem2008283(22):15319-15327.DOI:10.1074/jbc.M800021200.
[17]
Shi JYang YCheng A,et al.Metabolism of vascular smooth muscle cells in vascular diseases [J].Am J Physiol Heart Circ Physiol2020319(3):H613-H631.DOI:10.1152/ajpheart.00220.2020.
[18]
Zeng ZLYuan QZu X,et al.Insights into the role of mitochondria in vascular calcification[J].Front Cardiovasc Med2022(9):879752.DOI:10.3389/fcvm.2022.879752.
[19]
He LZhou QHuang Z,et al.PINK1/Parkin-mediated mitophagy promotes apelin-13-induced vascular smooth muscle cell proliferation by AMPKα and exacerbates atherosclerotic lesions[J].J Cell Physiol2019234(6):8668-8682.DOI:10.1002/jcp.27527.
[20]
Voelkl JEgli-Spichtig DAlesutan I,et al.Inflammation:a putative link between phosphate metabolism and cardiovascular disease[J].Clin Sci (Lond)2021135(1):201-227.DOI:10.1042/CS20190895.
[21]
Raikou VDKyriaki DGavriil S.Importance of serum phosphate in elderly patients with diabetes mellitus[J].World J Diabetes202011(10):416-424.DOI:10.4239/wjd.v11.i10.416.
[22]
Crouthamel MHLau WLLeaf EM,et al.Sodium-dependent phosphate cotransporters and phosphate-induced calcification of vascular smooth muscle cells:redundant roles for PiT-1 and PiT-2[J].Arterioscler Thromb Vasc Biol201333(11):2625-2632.DOI:10.1161/ATVBAHA.113.302249.
[23]
Nguyen NTNguyen TTDa Ly D, et al. Oxidative stress by Ca2+ overload is critical for phosphate-induced vascular calcification[J].Am J Physiol Heart Circ Physiol2020319(6):H1302-H1312.DOI:10.1152/ajpheart.00305.2020.
[24]
Rashdan NASim AMCui L,et al.Osteocalcin regulates arterial calcification via altered Wnt signaling and glucose metabolism[J].J Bone Miner Res202035(2):357-367.DOI:10.1002/jbmr.3888.
[25]
Lee SJJeong JYOh CJ,et al.Pyruvate dehydrogenase kinase 4 promotes vascular calcification via SMAD1/5/8 phosphorylation[J].Sci Rep2015(5):16577.DOI:10.1038/srep16577.
[26]
Saelens X, Festjens N, Vande Walle L, et al. Toxic proteins released from mitochondria in cell death[J].Oncogene200423(16):2861-2874.DOI:10.1038/sj.onc.1207523.
[27]
Hill MMAdrain CDuriez PJ,et al.Analysis of the composition,assembly kinetics and activity of native Apaf-1 apoptosomes[J].EMBO J200423(10):2134-2145.DOI:10.1038/sj.emboj.7600210.
[28]
Kim HKim HJLee K,et al.α-Lipoic acid attenuates vascular calcification via reversal of mitochondrial function and restoration of Gas6/Axl/Akt survival pathway[J].J Cell Mol Med201216(2):273-286.DOI:10.1111/j.1582-4934.2011.01294.x.
[29]
Cui LLi ZChang X,et al.Quercetin attenuates vascular calcification by inhibiting oxidative stress and mitochondrial fission[J].Vascul Pharmacol2017(88):21-29.DOI:10.1016/j.vph.2016.11.006.
[30]
Huang M, Zheng L, Xu H, et al. Oxidative stress contributes to vascular calcification in patients with chronic kidney disease[J].J Mol Cell Cardiol2020(138):256-268.DOI:10.1016/j.yjmcc.2019.12.006.
[31]
Chen NXDuan DO′Neill KD,et al.High glucose increases the expression of Cbfa1 and BMP-2 and enhances the calcification of vascular smooth muscle cells[J].Nephrol Dial Transplant200621(12):3435-3442.DOI:10.1093/ndt/gfl429.
[32]
Weinberg Sibony RSegev ODor S,et al.Overview of oxidative stress and inflammation in diabetes[J].J Diabetes202416(10):e70014.DOI:10.1111/1753-0407.70014.
[33]
Basta GLazzerini GDel Turco S,et al.At least 2 distinct pathways generating reactive oxygen species mediate vascular cell adhesion molecule-1 induction by advanced glycation end products[J].Arterioscler Thromb Vasc Biol200525(7):1401-1407.DOI:10.1161/01.ATV.0000167522.48370.5e.
[34]
Liu Y, Li J, Han Y, et al. Advanced glycation end-products suppress autophagy by AMPK/mTOR signaling pathway to promote vascular calcification[J].Mol Cell Biochem2020471(1-2):91-100.DOI:10.1007/s11010-020-03769-9.
[35]
Ma WQ, Han XQ, Wang Y, et al. Nε-carboxymethyl-lysine promotes calcium deposition in VSMCs via intracellular oxidative stress-induced PDK4 activation and alters glucose metabolism[J].Oncotarget20178(68):112841-112854.DOI:10.18632/oncotarget.22835.
[36]
Zhu YMa WQHan XQ,et al.Advanced glycation end products accelerate calcification in VSMCs through HIF-1α/PDK4 activation and suppress glucose metabolism[J].Sci Rep20188(1):13730.DOI:10.1038/s41598-018-31877-6.
[37]
Kay AM, Simpson CL, Stewart JA Jr. The role of AGE/RAGE signaling in diabetes-mediated vascular calcification[J].J Diabetes Res2016(2016):6809703.DOI:10.1155/2016/6809703.
[38]
Ishitobi M, Hosaka T, Morita N, et al. Serum lactate levels are associated with serum alanine aminotransferase and total bilirubin levels in patients with type 2 diabetes mellitus:a cross-sectional study[J].Diabetes Res Clin Pract2019(149):1-8.DOI:10.1016/j.diabres.2019.01.028.
[39]
Broskey NTZou KDohm GL,et al.Plasma lactate as a marker for metabolic health[J].Exerc Sport Sci Rev202048(3):119-124.DOI:10.1249/JES.0000000000000220.
[40]
Zhu YHan XQSun XJ,et al.Lactate accelerates vascular calcification through NR4A1-regulated mitochondrial fission and BNIP3-related mitophagy[J].Apoptosis202025(5/6):321-340.DOI:10.1007/s10495-020-01592-7.
[41]
Zhu YZhang JLYan XJ,et al. Exploring a new mechanism between lactate and VSMC calcification:PARP1/POLG/UCP2 signaling pathway and imbalance of mitochondrial homeostasis[J].Cell Death Dis202314(9):598.DOI:10.1038/s41419-023-06113-3.
[42]
Kozlov AM, Lone A, Betts DH, et al. Lactate preconditioning promotes a HIF-1α-mediated metabolic shift from OXPHOS to glycolysis in normal human diploid fibroblasts[J].Sci Rep202010(1):8388.DOI:10.1038/s41598-020-65193-9.
[43]
Tang FTChen SRWu XQ,et al.Hypercholesterolemia accelerates vascular calcification induced by excessive vitamin D via oxidative stress[J].Calcif Tissue Int200679(5):326-339.DOI:10.1007/s00223-006-0004-8.
[44]
Swiader ANahapetyan HFaccini J,et al.Mitophagy acts as a safeguard mechanism against human vascular smooth muscle cell apoptosis induced by atherogenic lipids[J].Oncotarget20167(20):28821-28835.DOI:10.18632/oncotarget.8936.
[45]
Dwyer JRSever NCarlson M,et al.Oxysterols are novel activators of the hedgehog signaling pathway in pluripotent mesenchymal cells[J].J Biol Chem2007282(12):8959-8968.DOI:10.1074/jbc.M611741200.
[46]
Brodeur MRBouvet CBarrette M,et al.Palmitic acid increases medial calcification by inducing oxidative stress[J].J Vasc Res201350(5):430-441.DOI:10.1159/000354235.
[47]
Shao JSCheng SLPingsterhaus JM,et al.Msx2 promotes cardiovascular calcification by activating paracrine Wnt signals[J].J Clin Invest2005115(5):1210-1220.DOI:10.1172/JCI24140.
[48]
Sun KTang XSong S,et al.Hyperoxalemia leads to oxidative stress in endothelial cells and mice with chronic kidney disease[J].Kidney Blood Press Res202146(3):377-386.DOI:10.1159/000516013.
[49]
Henze LALuong TBoehme B,et al.Impact of C-reactive protein on osteo-/chondrogenic transdifferentiation and calcification of vascular smooth muscle cells[J].Aging (Albany NY)201911(15):5445-5462.DOI:10.18632/aging.102130.
[50]
Raghuraman GHsiung JZuniga MC,et al.Eotaxin augments calcification in vascular smooth muscle cells[J].J Cell Biochem2017118(3):647-654.DOI:10.1002/jcb.25752.
[51]
Petsophonsakul P, Burgmaier M, Willems B, et al. Nicotine promotes vascular calcification via intracellular Ca2+-mediated,Nox5-induced oxidative stress,and extracellular vesicle release in vascular smooth muscle cells[J].Cardiovasc Res2022118(9):2196-2210.DOI:10.1093/cvr/cvab244.
[52]
Chen WRZhou YJSha Y,et al.Melatonin attenuates vascular calcification by inhibiting mitochondria fission via an AMPK/Drp1 signalling pathway[J].J Cell Mol Med202024(11):6043-6054.DOI:10.1111/jcmm.15157.
[53]
Ma WQSun XJWang Y,et al.Restoring mitochondrial biogenesis with metformin attenuates β-GP-induced phenotypic transformation of VSMCs into an osteogenic phenotype via inhibition of PDK4/oxidative stress-mediated apoptosis[J].Mol Cell Endocrinol2019(479):39-53.DOI:10.1016/j.mce.2018.08.012.
[54]
Zhang PLi YDu Y,et al.Resveratrol ameliorated vascular calcification by regulating Sirt-1 and Nrf2[J].Transplant Proc201648(10):3378-3386.DOI:10.1016/j.transproceed.2016.10.023.
[55]
Cui LZhou QZheng X,et al.Mitoquinone attenuates vascular calcification by suppressing oxidative stress and reducing apoptosis of vascular smooth muscle cells via the Keap1/Nrf2 pathway[J].Free Radic Biol Med2020(161):23-31.DOI:10.1016/j.freeradbiomed.2020.09.028.
[56]
Wang PWPang QZhou T,et al.Irisin alleviates vascular calcification by inhibiting VSMC osteoblastic transformation and mitochondria dysfunction via AMPK/Drp1 signaling pathway in chronic kidney disease[J].Atherosclerosis2022(346):36-45.DOI:10.1016/j.atherosclerosis.2022.02.007.
[1] 周圆圆, 周怡, 段亚阳, 张怡卿, 朱峰宇, 张超学. 低强度超声缓解顺铂所致小鼠卵巢损伤的实验研究[J/OL]. 中华医学超声杂志(电子版), 2024, 21(12): 1132-1141.
[2] 张凯, 乔永杰, 林志强, 刘健, 邓泽群, 谭飞, 曾健康, 李嘉欢, 李培杰, 周胜虎. 假体周围骨溶解中巨噬细胞极化的机制研究进展[J/OL]. 中华关节外科杂志(电子版), 2024, 18(05): 618-625.
[3] 黄凤, 李文润, 冉永红, 谌莉, 刘泓伽, 王秋池, 郝玉徽. 贫铀对线粒体损伤影响的研究进展[J/OL]. 中华损伤与修复杂志(电子版), 2025, 20(02): 179-183.
[4] 王馨悦, 王卓然, 古丽莎. 氧化纳米铈促进氧化应激状态下口腔骨缺损修复的研究进展[J/OL]. 中华口腔医学研究杂志(电子版), 2025, 19(01): 62-69.
[5] 李一萱, 李美和, 郑瑾. 肾移植缺血再灌注损伤机制及其对移植肾的影响[J/OL]. 中华移植杂志(电子版), 2025, 19(01): 43-49.
[6] 郭倩男, 史嘉玮, 董念国. T细胞不同代谢方式在移植排斥反应中的研究进展[J/OL]. 中华移植杂志(电子版), 2024, 18(05): 315-320.
[7] 白玉杰, 王枭, 林宁, 刘佳姣, 罗书泓, 冯健, 李福祥. 甲基胞嘧啶双加氧酶2 对低氧人脐静脉内皮细胞损伤的作用研究[J/OL]. 中华肺部疾病杂志(电子版), 2025, 18(03): 369-374.
[8] 吕园园, 高辰旸, 徐永君. 纳米金棒对A549 细胞的毒性效应及其对自噬的影响[J/OL]. 中华细胞与干细胞杂志(电子版), 2025, 15(01): 20-29.
[9] 杜霞, 马梦青, 曹长春. 造影剂诱导的急性肾损伤的发病机制及干预靶点研究进展[J/OL]. 中华肾病研究电子杂志, 2024, 13(05): 279-282.
[10] 李佳曦, 刘子源, 李学民. 二甲双胍对年龄相关性白内障影响的研究进展[J/OL]. 中华眼科医学杂志(电子版), 2024, 14(04): 252-256.
[11] 陈月阳, 王景景, 王淑莹, 杨以太, 李泽萌, 胡迪, 周蓬勃, 李伟, 任党利, 孙洪涛. 五苓散对缺氧大鼠高原脑水肿的改善作用及机制研究[J/OL]. 中华神经创伤外科电子杂志, 2025, 11(02): 86-93.
[12] 李京, 牛博, 刘晓蓓, 魏新雪, 黄荣. circ-SESN2 沉默靶向调控miRNA-23a-5p/ULK1 在神经细胞氧化应激损伤中的作用机制研究[J/OL]. 中华神经创伤外科电子杂志, 2024, 10(05): 263-272.
[13] 唐建新, 邓晋, 谢威, 唐夏玉, 王斯旗. 星状神经节阻滞联合右美托咪定在胃肠手术中的麻醉效果及其与胃肠功能相关性研究[J/OL]. 中华消化病与影像杂志(电子版), 2025, 15(04): 405-411.
[14] 光雪珂, 刘承云, 卢伟琳. 线粒体功能障碍与老年人缺血性脑卒中相关信号通路关系研究进展[J/OL]. 中华老年病研究电子杂志, 2025, 12(01): 41-47.
[15] 庞淇丹, 崔玮, 唐涛, 姜德春, 李深. 检测脑缺血再灌注损伤的探针及技术进展[J/OL]. 中华脑血管病杂志(电子版), 2025, 19(02): 149-154.
阅读次数
全文


摘要


AI


AI小编
你好!我是《中华医学电子期刊资源库》AI小编,有什么可以帮您的吗?