糖尿病常伴随血管内皮损伤,显著加速血管病理进程,但其分子机制尚未阐明。已有报道证实,特殊的补体分子在血管损伤中扮演重要角色。该实验室既往研究发现,补体分子C1qa(Component 1, q Subcomponent, A chain)在糖尿病小鼠主动脉内皮层高表达,并且表达量随着心血管疾病的发展而增多。因此,该研究利用链脲佐菌素(streptozocin, STZ)诱导糖尿病小鼠模型,并研究了C1qa分子的食源性抑制剂,即五没食子酰葡萄糖(1,2,3,4,6-O-pentagalloylglucose, PGG)对糖尿病血管内皮的修复作用。结果表明,外源C1qa刺激会显著增加血管内皮的活性氧(reactive oxygen species, ROS)水平,同时降低主动脉内皮依赖性舒张功能。相似地,糖尿病模型中,血管内皮C1qa的高含量伴随着ROS的过量合成,主动脉血管段的内皮依赖性舒张显著降低。而PGG灌胃3周后,糖尿病小鼠血糖下降至15.36 mmol/L,主动脉内皮C1qa表达量显著降低,ROS生成量减少了52.41%,血管内皮舒张率由47.06%升到68.41%。同时,NADPH氧化酶(NOX2/NOX4)通路表达下调,提示ROS生成的关键通路被抑制,血管内皮氧化应激损伤显著减轻。因此,活性分子PGG靶向抑制C1qa,有利于修复糖尿病小鼠主动脉内皮损伤。
Diabetes mellitus frequently causes endothelial damage, dramatically accelerating the progression of vascular diseases.However, the molecular mechanisms remain to be defined.Specific complement molecules have been demonstrated to play an important role in vascular injury.Previous research in our laboratory showed that the aortic endothelium of diabetic mice contained high levels of C1qa, which increased with the development of cardiovascular diseases.To investigate the effect of a dietary inhibitor of C1qa, 1,2,3,4,6-O-pentagalloylglucose (PGG), on diabetic vascular endothelial repair, we established a streptozocin (STZ) diabetic mice model.Results showed that exogenous C1qa stimulation significantly increased vascular endothelial reactive oxygen species (ROS) levels while decreasing aortic endothelium-dependent diastolic function.Likewise, in diabetic mice, high vascular endothelial C1qa levels were associated with excessive ROS synthesis and significantly reduced endothelium-dependent diastole in aortic segments.Nevertheless, three weeks of PGG gavage in diabetic mice considerably reduced aortic endothelial C1qa expression, decreased blood glucose to 15.36 mmol/L, a 52.41% reduction in ROS production, and an increased rate in vascular endothelial diastolic from 47.06% to 68.41%.Simultaneously, PGG downregulated the expression of the NADPH oxidase pathway (NOX2/NOX4), indicating that it inhibited the essential pathway of ROS generation.Thus, vascular endothelial damage from oxidative stress got a substantial attenuation.Hence, PGG-targeted inhibition of C1qa is beneficial for repairing aortic endothelial dysfunction in diabetic mice.
[1] KNAPP M, TU X, WU R X.Vascular endothelial dysfunction, a major mediator in diabetic cardiomyopathy[J].Acta Pharmacologica Sinica, 2019, 40(1):1-8.
[2] KAUR R, KAUR M, SINGH J.Endothelial dysfunction and platelet hyperactivity in type 2 diabetes mellitus:Molecular insights and therapeutic strategies[J].Cardiovascular Diabetology, 2018, 17(1):121.
[3] MARZIANO C, GENET G, HIRSCHI K K.Vascular endothelial cell specification in health and disease[J].Angiogenesis, 2021, 24(2):213-236.
[4] DAIBER A, STEVEN S, WEBER A, et al.Targeting vascular (endothelial) dysfunction[J].British Journal of Pharmacology, 2017, 174(12):1591-1619.
[5] MARTIN-VENTURA J L, MARTINEZ-LOPEZ D, ROLDAN-MONTERO R, et al.Role of complement system in pathological remodeling of the vascular wall[J].Molecular Immunology, 2019, 114:207-215.
[6] KISHORE U, REID K B.C1q:Structure, function, and receptors[J].Immunopharmacology, 2000, 49(1-2):159-170.
[7] OGAWA T, SHICHINO S, UEHA S, et al.Complement protein C1q activates lung fibroblasts and exacerbates silica-induced pulmonary fibrosis in mice[J].Biochemical and Biophysical Research Communications.2022, 603:88-93.
[8] SUMIDA T, NAITO A T, NOMURA S, et al.Complement C1q-induced activation of β-catenin signalling causes hypertensive arterial remodelling[J].Nature Communications, 2015, 6:6241.
[9] 许醒, 蔡林峰, 张倩楠, 等.单细胞与空间转录组分析研究进展[J].分析测试学报, 2022, 41(9):1322-1334.
XU X, CAI L F, ZHANG Q N, et al.Progress on single-cell and spatial transcriptome analysis[J].Journal of Instrumental Analysis, 2022, 41(9):1322-1334.
[10] LIU F Z, LI Y B, YANG Y, et al.Study on mechanism of matrine in treatment of COVID-19 combined with liver injury by network pharmacology and molecular docking technology[J].Drug Delivery, 2021, 28(1):325-342.
[11] DING S M, QIU H M, HUANG J J, et al.Activation of 20-HETE/PPARs involved in Reno-therapeutic effect of naringenin on diabetic nephropathy[J].Chemico-Biological Interactions, 2019, 307:116-124.
[12] CHAI Y B, LEE H J, SHAIK A A, et al.Penta-O-galloyl-beta-D-glucose induces G1 arrest and DNA replicative S-phase arrest independently of cyclin-dependent kinase inhibitor 1A, cyclin-dependent kinase inhibitor 1B and P53 in human breast cancer cells and is orally active against triple negative xenograft growth[J].Breast Cancer Research:BCR, 2010, 12(5):R67.
[13] ZHOU C X, TAN Y, XU B J, et al.3, 4′, 5-Trimethoxy-trans-stilbene alleviates endothelial dysfunction in diabetic and obese mice via activation of the AMPK/SIRT1/eNOS pathway[J].Antioxidants, 2022, 11(7):1286.
[14] TAREK B, BRUGGISSER J, CATTALANI F, et al.Platelet endothelial cell adhesion molecule 1 (CD31) is essential for Clostridium perfringens beta-toxin mediated cytotoxicity in human endothelial and monocytic cells[J].Toxins, 2021, 13(12):893.
[15] CAO J, JIANG X, PENG X.Forkhead box M1 inhibits endothelial cell apoptosis and cell-cycle arrest through ROS generation[J].International Journal of Clinical and Experimental Pathology, 2018, 11(10):4899-4907.
[16] HE D X, MAO A Q, ZHENG C B, et al.Aortic heterogeneity across segments and under high fat/salt/glucose conditions at the single-cell level[J].National Science Review, 2020, 7(5):881-896.
[17] SENONER T, DICHTL W.Oxidative stress in cardiovascular diseases:Still a therapeutic target?[J].Nutrients, 2019, 11(9):2090.
[18] GODO S, SHIMOKAWA H.Endothelial functions[J].Arteriosclerosis Thrombosis Vascular Biology, 2017, 37(9):108-114.
[19] MITTAL M, SIDDIQUI M R, TRAN K, et al.Reactive oxygen species in inflammation and tissue injury[J].Antioxidants & Redox Signaling, 2014, 20(7):1126-1167.
[20] SATHYANARAYANA A R, LU C K, LIAW C C, et al.1, 2, 3, 4, 6-Penta-O-galloyl-D-glucose interrupts the early adipocyte lifecycle and attenuates adiposity and hepatic steatosis in mice with diet-induced obesity[J].International Journal of Molecular Sciences, 2022, 23(7):4052.
[21] MUKAI E R, FUJIMOTO S, INAGAKI N.Role of reactive oxygen species in glucose metabolism disorder in diabetic pancreatic β-cells[J].Biomolecules, 2022, 12(9):1228.
[22] CLYNE A M.Endothelial response to glucose:Dysfunction, metabolism, and transport[J].Biochemical Society Transactions, 2021, 49(1):313-325.
[23] STURTZEL C.Endothelial Cells[M]//Advances in Experimental Medicine and Biology.Cham:Springer International Publishing, 2017:71-91.
[24] ZHENG D D, LIU J, PIAO H L, et al.ROS-triggered endothelial cell death mechanisms:Focus on pyroptosis, parthanatos, and ferroptosis[J].Frontiers in Immunology, 2022, 13:1039241.
