Research Progress of Iron Death in Cardiomyopathy
-
摘要: 心肌病是一组具有多种特定表型的异质性心肌疾病,严重者会引起心血管性死亡或进行性心力衰竭。由于这类疾病的严重性和复杂性,寻找新的调节机制来防治心肌病显得尤为紧迫。铁死亡是一种不同于其他形式的铁依赖性的细胞程序性死亡形式,其特征是铁依赖性脂质过氧化物的积累。研究表明,铁死亡可通过不同的信号通路参与心肌病的发生和进展。因此通过靶向调控铁死亡是防治心肌病的一种新策略。就铁死亡的发生机制及其在心肌病中的重要作用进行综述,以期寻找铁死亡与心肌病之间的潜在联系,为今后各种心肌病的治疗提供更多思路。Abstract: Cardiomyopathy is a group of heterogeneous myocardial diseases with a variety of specific phenotypes that can lead to cardiovascular death or progressive heart failure in severe cases. Because of the severity and complexity of these diseases, the search for new regulatory mechanisms to prevent and treat cardiomyopathy is particularly urgent. Iron death is a form of programmed cell death that differs from other forms of iron dependence and is characterized by the accumulation of iron-dependent lipid peroxides. Studies have shown that iron death can be involved in the occurrence and progression of cardiomyopathy through different signaling pathways. Therefore, targeted regulation of iron death is a new strategy to prevent cardiomyopathy. In this paper, the mechanism of iron death and its important role in cardiomyopathy were reviewed to find the potential relationship between iron death and cardiomyopathy and provide more ideas for the treatment of various cardiomyopathies in the future.
-
Key words:
- Cardiomyopathy /
- Ferroptosis /
- Cell death /
- Iron metabolism
-
脑膜瘤是起源于脑膜的肿瘤,发病率高,约占颅内原发肿瘤的30%[1]。脑膜瘤以手术治疗为主,手术时间长、创伤大,导致免疫系统激活引起全身炎症反应,使体内炎症介质水平增高,导致术后严重的神经系统并发症[2]。
右美托嘧啶(dexmedetomidine,Dex)是现在术中常用的α2-肾上腺素受体激动剂[3-4],在围术期对多脏器都具有保护作用,改善患者预后[5]。在神经外科手术中应用,可稳定血流动力学,减轻炎症反应,抑制自由基的产生,从而起到脑保护的作用[6-8]。盐酸纳布啡是一种阿片类兴奋-拮抗剂,兴奋κ受体发挥镇静镇痛作用,部分拮抗μ受体。纳布啡在手术中可抑制炎症,使术中生命体征更平稳[9]。本研究通过联合应用Dex与纳布啡和单用Dex比较,探讨Dex联合纳布啡对脑膜瘤患者炎症及术后认知功能的影响。
1. 对象与方法
1.1 研究对象
本研究通过昆明医科大学第一附属医院伦理委员会审核,并取得患者及其家属的书面同意。纳入标准:年龄24~54岁,ASAⅠ~Ⅱ级,无其他系统疾病,无药物依赖史。排除标准:重要脏器失代偿者;对计划用药过敏者;无法完成简易精神状态检查表(MMSE)[10]或术前评分 < 24分的患者;围术期输血者;围术期应用影响免疫功能药物者;手术失败者。选取符合标准且于2018年7月至2019年3月昆明医科大学第一附属医院行择期脑膜瘤切除术治疗的患者共60例。采用随机数字表法将符合标准的患者分成两组:Dex联合纳布啡组(DN组)和Dex组(D组)。DN组男16例,女14例,平均(41.93±10.62)岁,平均手术时长(250±27.36) min。D组男17例,女13例,平均(40.33±8.56)岁,平均手术时长(257.20±29.13) min。两组患者年龄、性别构成、手术时长等一般资料比较,差异无统计学意义(P > 0.05)。
1.2 研究方法
1.2.1 麻醉方法
常规禁饮禁食,未使用麻醉前用药。入室后监测HR、MAP、ECG、SpO2、BIS。两组患者均予以相同的麻醉方案,采用麻醉机面罩吸氧FiO2 100%,氧流量3~4 L/min。麻醉诱导:依次静脉推注咪达唑仑2 mg,芬太尼3~4 µg/kg,丙泊酚1.5~2.5 mg/kg,罗库溴铵0.6~0.8 mg/kg诱导,诱导结束经口插入相应(ID 6.5~8.0)钢丝导管。插管后行右颈内静脉穿刺置管,测CVP。麻醉维持:瑞芬太尼0.25~2 µg/(kg·min)、丙泊酚4~12 mg/(kg·h)持续微量泵泵入,维持BIS值在40~60之间。DN组在切皮前5 min静脉注射盐酸纳布啡0.2 mg/kg,于诱导前30 min予Dex1 µg/kg泵注10 min后改为0.5 µg/(kg·h),持续泵注至缝合硬脑膜前。D组中Dex给予方案同前,不给纳布啡。
术中若MAP、HR平稳,BIS值超过50则调大丙泊酚泵注量;若BIS值40~50,MAP、HR升高则调大瑞芬太尼泵注量;若心动过缓(HR < 50次/min)静注阿托品0.3~0.5 mg,低血压(平均血压低于基础值的70%和(或)MAP < 60 mmHg)予麻黄碱6~12 mg。
1.2.2 观察指标
记录术前(T1),诱导插管时(T2),切皮时(T3),清醒拔管时(T4)的心率血压。于术前(t1),术后2 h (t2),术后6 h (t3),术后24 h (t4)采集中心静脉血液2 mL,用流式细胞仪检测炎症相关因子白介素6(IL-6)、白介素10 (IL-10)、肿瘤坏死因子α(TNF-α)浓度。在术前、术后6 h、术后24 h、术后3 d、术后6 d进行MMSE评分。MMSE评分 < 24分者,判定为术后认知功能障碍(postoperative cognitive dysfunction,POCD)。
1.3 统计学处理
采用SPSS统计软件分析实验结果。计量资料服从正态分布用均数±标准差描述,两组不同时间点比较采用重复测量的方差分析,如有差异两组间比较采用独立样本t检验。P < 0.05为差异有统计学意义(α = 0.05)。
2. 结果
2.1 两组心率、平均动脉压、住院时间比较
与D组相比,DN组拔管后HR、MAP均较低(P < 0.05)。与术前相比,DN组插管时、切皮时HR、MAP均明显降低(P < 0.05);D组插管时MAP明显下降(P < 0.05),切皮时、拔管时HR、MAP明显下降(P < 0.05)。DN组住院时间平均(11.37±1.72) d,D组住院时间平均(12.63±1.65) d,DN组住院时间明显缩短(P < 0.05),见表1。
表 1 两组术中HR、MAP和住院时间比较($\bar x \pm s$ )Table 1. Comparison of intraoperative HR,MAP and hospitalization time between the two groups ($\bar x \pm s$ )组别 观察指标 术前 插管时 切皮时 拔管时 DN组 HR (次/min) 82.23 ± 4.85 77.03 ± 7.99# 77.73 ± 7.58# 81.03 ± 5.91* MAP (mmHg) 82.4 ± 4.35 74.77 ± 3.98# 77.70 ± 3.46# 82.50 ± 4.54* D组 HR (次/min) 82.43 ± 4.57 78.97 ± 6.81 78.83 ± 7.95# 87.23 ± 7.66# MAP (mmHg) 81.83 ± 4.28 74.93 ± 4.71# 77.93 ± 4.43# 85.30 ± 5.23# 与D组比较,*P < 0.05;与同组术前比较,#P < 0.05; 2.2 两组炎症反应比较
与D组相比,DN组IL-6、IL-10、TNF-α浓度在T1、T2、T3、T4时刻浓度较低(P < 0.05);与同组术前IL-6、IL-10、TNF-α浓度相比较,除T4时刻TNF-α浓度差异无统计学意义(P > 0.05),差异有统计学意义(P < 0.05)。DN组IL-6、IL-10、TNF-α浓度上升较D组小,见表2。
表 2 两组相同时间点炎症因子水平比较[($ {\bar{{x}}} \pm s$ ),pg/mL]Table 2. Comparison of inflammatory factor levels between the two groups at the same time point [($ {\bar{{x}}} \pm s$ ),pg/mL]组别 术前 2 h 6 h 24 h IL-6 IL-10 TNF-α IL-6 IL-10 TNF-α IL-6 IL-10 TNF-α IL-6 IL-10 TNF-α DN组 1.85±0.28 1.74±0.16 0.40±0.20 10.04±1.84*# 24.12±1.41*# 0.16±0.11*# 25.76±1.25*# 2.55±0.85*# 0.27±0.07*# 22.30±5.48*# 2.43±0.36*# 0.39±0.09* D组 1.94±0.38 1.75±0.15 0.38±0.17 18.26±2.34# 38.01±1.97# 0.60±0.08# 35.72±6.10# 11.59±1.34# 0.71±0.12# 49.58±5.51# 5.41±0.34# 0.79±0.11# 与D组比较,*P < 0.05;与同组术前比较,#P < 0.05。 2.3 两组术后认知功能比较
与D组相比,DN组术后6 h、24 h MMSE简易智力状态检查量表评分明显较高(P < 0.05);与术前相比,DN组6 h MMSE评分明显较低(P < 0.05),D组6 h、24 h MMSE评分明显较低(P < 0.05),见表3。
表 3 两组术后认知功能MMSE评分比较[(${\bar{{x}}}\pm s$ ),分]Table 3. Comparison of MMSE scores of postoperative cognitive function between the two groups [(${\bar{{x}}}\pm s$ ),scores]组别 术前 术后6 h 术后24 h 术后3 d 术后6 d DN组 27.37 ± 1.73 25.93 ± 2.18*# 26.33 ± 2.37* 26.77 ± 1.52 26.97 ± 1.71 D组 26.5 ± 1.93 24.80 ± 1.67# 25.10 ± 1.81# 27.33 ± 2.09 27.10 ± 1.79 与D组比较,*P < 0.05;与同组术前比较,#P < 0.05。 3. 讨论
脑膜瘤是起源于脑膜及脑膜间隙的肿瘤,多为良性,呈膨胀性生长。根据肿瘤位置不同,可以出现头痛、癫痫,视力、视野、嗅觉或听觉障碍及肢体运动障碍等[11]。手术切除是脑膜瘤最有效的治疗手段。
Dex与大脑蓝斑受体作用发挥镇静作用[12];同时,Dex通过结合脊髓后角α2受体抑制疼痛冲动向中枢传递,有一定的镇痛作用[13]。Ye Cai等[14]的研究表明α2受体激动剂可改善缺血性脑损伤的预后。纳布啡属吗啡喃类,是一种激动–拮抗镇痛药,结构上类似于阿片受体拮抗剂纳洛酮和强效阿片类镇痛药羟吗啡酮,镇痛效价与吗啡类似,但副作用较少[15]。研究发现,使用纳布啡可更有效的缓解神经外科手术后的疼痛[16]。本研究中,笔者对比Dex联合纳布啡和单独用于脑膜瘤手术中,发现联合用药组术中生命体征更稳定,术后生命体征与术前差异更小,住院时间缩短。保持稳定的生命体征有利于维持患者器官灌注稳定,减少不良预后,说明联合用药更有利于维持生命体征稳定。
颅内病变或手术可激活蓝斑去甲肾上腺素轴和下丘脑-垂体-肾上腺轴以及刺激免疫系统,导致激素和促炎细胞因子分泌增加[17]。TNF-α,IL-6是中枢神经系统神经炎症的主要介质,并且首先在缺血性脑损伤的急性期引发[18]。适当释放炎症介质与神经保护有关但过度炎症反应可能导致神经细胞肿胀和坏死。Dex可通过Nrf2信号通路减轻创伤性脑损伤后神经炎症,显着下调炎症反应因子TNF-α,IL-1β和NF-κB以及IL-6[19]。纳布啡用于老年胸科手术中可使患者血清中TNF-α和IL-6浓度降低[20]。笔者发现与D组相比,DN组在相同时刻IL-6、IL-10、TNF-α浓度较低,与同组术前比较,DN组IL-6、IL-10、TNF-α浓度上升较D组小。
术后认知功能障碍(postoperative cognitive dysfunction,POCD)是指术后出现的人格、社交能力及认知能力和技巧的变化,表现为精神错乱、焦虑、人格的改变以及记忆受损等[21-22]。研究发现,在老年髋关节手术中,右美托咪定镇静的患者术后谵妄和术后认知功能障碍的发生率都较丙泊酚更低较低,出院时间更短[23]。笔者发现,两组在术后24 h内MMSE评分均较术前降低,但联合用药较单用Dex MMSE评分较高,术后认知功能恢复较快。说明联合用药更有利于患者术后认知功能恢复。
联合用药可降低患者血清中TNF-α,IL-6和IL-10水平,减轻患者全身炎症反应。研究发现,目前认为术后认知功能障碍可能的机制与炎症密切相关,炎性因子以直接通过血脑屏障破坏或激活多种信号通路等方式引发中枢系统炎症[24]。炎症因子直接或间接影响方患者的认知功能,引发POCD[25]。所以,笔者认为患者MMSE评分差异与联合应用右Dex及纳布啡降低患者全身炎症反应有关。
综上所述,在脑膜瘤术中,联合应有Dex和纳布啡较单独应用Dex可降低患者全身炎症反应,更有利于维持术中术后生命体征平稳,患者术后苏醒更快,住院时间更短,是更有利的麻醉用药方式。
-
[1] Boyle A J,Shih H,Hwang J,et al. Cardiomyopathy of aging in the mammalian heart is characterized by myocardial hypertrophy,fibrosis and a predisposition towards cardiomyocyte apoptosis and autophagy[J]. Experimental Gerontology,2011,46(7):549-559. doi: 10.1016/j.exger.2011.02.010 [2] Elliott P,Andersson B,Arbustini E,et al. Classification of the cardiomyopathies: A position statement from the european society of cardiology working group on myocardial and pericardial diseases[J]. European Heart Journal,2007,29(2):270-276. doi: 10.1093/eurheartj/ehm342 [3] Djulbegovic M B,Uversky V N. Ferroptosis – An iron- and disorder-dependent programmed cell death[J]. International Journal of Biological Macromolecules,2019,135:1052-1069. doi: 10.1016/j.ijbiomac.2019.05.221 [4] Kapralov A A,Yang Q,Dar H H,et al. Redox lipid reprogramming commands susceptibility of macrophages and microglia to ferroptotic death.[J]. Nature Chemical Biology,2020,16(3):278-290. doi: 10.1038/s41589-019-0462-8 [5] Jiang X,Stockwell B R,Conrad M. Ferroptosis: Mechanisms,biology,and role in disease[J]. Nature Reviews. Molecular Cell Biology,2021,22(4):266-282. doi: 10.1038/s41580-020-00324-8 [6] Bannai S,Kitamura E. Transport interaction of L-cystine and L-glutamate in human diploid fibroblasts in culture.[J]. Biological Chemistry,1980,255(6):2372-2376. doi: 10.1016/S0021-9258(19)85901-X [7] Yang W S,Stockwell B R. Synthetic lethal screening identifies compounds activating iron-dependent,nonapoptotic cell death in oncogenic-RAS-harboring cancer cells[J]. Chemistry & Biology,2008,15(3):234-245. [8] Dixon S J,Lemberg K M,Lamprecht M R,et al. Ferroptosis: an iron-dependent form of non-apoptotic cell death[J]. Cell,2012,149(5):1060-1072. doi: 10.1016/j.cell.2012.03.042 [9] Anderson G J,Vulpe C D. Mammalian iron transport[J]. Cellular and Molecular Life Sciences,2009,66(20):3241-3261. doi: 10.1007/s00018-009-0051-1 [10] Torti S V,Torti F M. Iron and cancer: 2020 vision[J]. Cancer Research,2020,80(24):5435-5448. doi: 10.1158/0008-5472.CAN-20-2017 [11] Dixon S J,Stockwell B R. The role of iron and reactive oxygen species in cell death[J]. Nature Chemical Biology,2014,10(1):9-17. doi: 10.1038/nchembio.1416 [12] Gao M,Monian P,Pan Q,et al. Ferroptosis is an autophagic cell death process[J]. Cell Research,2016,26(9):1021-1032. doi: 10.1038/cr.2016.95 [13] Bridges R J,Natale N R,Patel S A. System xc-cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS[J]. British Journal of Pharmacology,2012,165(1):20-34. doi: 10.1111/j.1476-5381.2011.01480.x [14] Shah R,Margison K,Pratt D A. The potency of diarylamine radical-trapping antioxidants as inhibitors of ferroptosis underscores the role of autoxidation in the mechanism of cell death[J]. ACS Chemical Biology,2017,12(10):2538-2545. doi: 10.1021/acschembio.7b00730 [15] Had-Aissouni L. Maintenance of antioxidant defenses of brain cells: plasma membrane glutamate transporters and beyond[J]. Amino Acids,2012,42(1):159-161. doi: 10.1007/s00726-011-0860-z [16] Yang W S,SriRamaratnam R,Welsch M E,et al. Regulation of ferroptotic cancer cell death by GPX4[J]. Cell,2014,156(1-2):317-331. [17] Yang W S,Stockwell B R. Ferroptosis: death by lipid peroxidation[J]. Trends in Cell Biology,2016,26(3):165-176. doi: 10.1016/j.tcb.2015.10.014 [18] Shimada K,Skouta R,Kaplan A,et al. Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis[J]. Nature Chemical Biology,2016,12(7):497-503. doi: 10.1038/nchembio.2079 [19] Hassannia B,Vandenabeele P,Vanden Berghe T. Targeting ferroptosis to iron out cancer[J]. Cancer Cell,2019,35(6):830-849. doi: 10.1016/j.ccell.2019.04.002 [20] Yang W S,Kim K J,Gaschler M M,et al. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis[J]. Proceedings of the National Academy of Sciences of the United States of America,2016,113(34):E4966-E4975. [21] Kagan V E,Mao G,Qu F,et al. Oxidized arachidonic/adrenic phosphatidylethanolamines navigate cells to ferroptosis[J]. Nature Chemical Biology,2017,13(1):81-90. doi: 10.1038/nchembio.2238 [22] Dixon S J,Winter G E,Musavi L S,et al. Human haploid cell genetics reveals roles for lipid metabolism genes in nonapoptotic cell death[J]. ACS Chemical Biology,2015,10(7):1604-1609. doi: 10.1021/acschembio.5b00245 [23] Golej D L,Askari B,Kramer F,et al. Long-chain acyl-CoA synthetase 4 modulates prostaglandin E2 release from human arterial smooth muscle cells[J]. Journal of Lipid Research,2011,52(4):782-793. doi: 10.1194/jlr.M013292 [24] Tadokoro T, Ikeda M, Ide T, et al. Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity[J]. JCI Insight, 2020, 5(9): e132747. [25] Bersuker K,Hendricks J,Li Z,et al. The CoQ oxidoreductase FSP1 acts in parallel to GPX4 to inhibit ferroptosis[J]. Nature,2019,575(7784):688-692. doi: 10.1038/s41586-019-1705-2 [26] Dai E,Zhang W,Cong D,et al. AIFM2 blocks ferroptosis independent of ubiquinol metabolism[J]. Biochemical and Biophysical Research Communications,2020,523(4):966-971. doi: 10.1016/j.bbrc.2020.01.066 [27] McGowan J V,Chung R,Maulik A,et al. Anthracycline chemotherapy and cardiotoxicity[J]. Cardiovascular Drugs and Therapy,2017,31(1):63-75. doi: 10.1007/s10557-016-6711-0 [28] Wang G,Hamid T,Keith R J,et al. Cardioprotective and anti-apoptotic effects of heme oxygenase-1in the failing heart[J]. Circulation,2010,121(17):1912-1925. doi: 10.1161/CIRCULATIONAHA.109.905471 [29] Liu Y,Zeng L,Yang Y,et al. Acyl-CoA thioesterase 1 prevents cardiomyocytes from doxorubicin-induced ferroptosis via shaping the lipid composition[J]. Cell Death & Disease,2020,11(9):756. [30] Rhee J W,Yi H,Thomas D,et al. Modeling secondary iron overload cardiomyopathy with human induced pluripotent stem cell-derived cardiomyocytes[J]. Cell Reports,2020,32(2):107886. doi: 10.1016/j.celrep.2020.107886 [31] DeHart D N,Fang D,Heslop K,et al. Opening of voltage dependent anion channels promotes reactive oxygen species generation,mitochondrial dysfunction and cell death in cancer cells[J]. Biochemical Pharmacology,2018,148(1):155-162. doi: 10.1016/j.bcp.2017.12.022 [32] Wang C,Yuan W,Hu A,et al. Dexmedetomidine alleviated sepsis-induced myocardial ferroptosis and septic heart injury[J]. Molecular Medicine Reports,2020,22(1):175-184. doi: 10.3892/mmr.2020.11114 [33] A Thandavarayan R,V Giridharan V,Watanabe K,et al. Diabetic cardiomyopathy and oxidative stress: Role of antioxidants[J]. Cardiovascular & Hematological Agents in Medicinal Chemistry,2011,9(4):225-230. [34] Zang H,Wu W,Qi L,et al. Autophagy inhibition enables nrf2 to exaggerate the progression of diabetic cardiomyopathy in mice[J]. Diabetes,2020,69(12):2720-2734. doi: 10.2337/db19-1176 [35] Schultheis J, Beckmann D, Mulac D, et al. Nrf2 activation protects mouse beta cells from glucolipotoxicity by restoring mitochondrial function and physiological redox balance[J]. Oxidative Medicine and Cellular Longevity, 2019, 2019: 7518510. [36] Bao L,Jin Y,Han J,et al. Berberine regulates GPX4 to inhibit ferroptosis of islet β cells[J]. Planta Medica,2023,89(3):254-261. doi: 10.1055/a-1939-7417 [37] Mei S,Xia Z,Qiu Z,et al. Shenmai injection attenuates myocardial ischemia/reperfusion injury by targeting Nrf2/GPX4 signalling-mediated ferroptosis[J]. Chinese Journal of Integrative Medicine,2022,28(11):983-991. doi: 10.1007/s11655-022-3620-x [38] Li K. Iron pathophysiology in friedreich's ataxia[J]. Advances in Experimental Medicine and Biology,2019,1173(1):125-143. [39] Zhang S,Napierala M,Napierala J S. Therapeutic prospects for Friedreich’s ataxia[J]. Trends in Pharmacological Sciences,2019,40(4):229-233. doi: 10.1016/j.tips.2019.02.001 [40] Emond M,Lepage G,Vanasse M,et al. Increased levels of plasma malondialdehyde in Friedreich ataxia[J]. Neurology,2000,55(11):1752-1753. doi: 10.1212/WNL.55.11.1752 [41] Kahn-Kirby A H,Amagata A,Maeder C I,et al. Targeting ferroptosis: A novel therapeutic strategy for the treatment of mitochondrial disease-related epilepsy[J]. PLoS ONE,2019,14(3):e0214250. doi: 10.1371/journal.pone.0214250 期刊类型引用(1)
1. 卢磊,毕小刚,张艳,田丰. 两种内镜逆行阑尾炎治疗术的临床应用效果比较. 中国内镜杂志. 2024(11): 59-65 . 百度学术
其他类型引用(0)
-

计量
- 文章访问数: 1270
- HTML全文浏览量: 694
- PDF下载量: 34
- 被引次数: 1