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通讯作者:

董尔丹(1959-),男,河北唐山人,博士研究生,从事心血管基础研究和科技工程管理研究。E-mail:donged@bjmu.edu.cn

中图分类号:R593.22

文献标识码:A

文章编号:62-1218(2020)01-0001-07

DOI:10.12287/j.issn.2096-8965.20200101

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目录contents

    摘要

    全球心血管疾病发病率和死亡率不断增加。病理性心脏重塑在心血管疾病发生发展中发挥重要作用。越来越多的研究关注在病理性心脏重塑中心脏代谢的改变。心脏肥大和心力衰竭时心脏代谢紊乱,心肌从脂肪酸为主的代谢特征转变为葡萄糖为主的代谢特征,心脏结构和功能发生异常。本文综述了病理性心脏重塑中脂肪酸、葡萄糖和氨基酸不同底物代谢变化特征及其对心脏功能的影响。基于病理性重塑的代谢改变分析潜在干预靶点,从代谢调节的角度为药物研发提供新路径和理论依据,以改善心脏肥大和心力衰竭患者的预后。

    Abstract

    The morbidity and mortality of cardiovascular diseases are increasing globally. Pathological cardiac remodeling plays an important role in the development of cardiovascular diseases. More and more investigations focus on the alterations of cardiac metabolism in pathological cardiac remodeling. Cardiac substrate metabolism is severely impaired during cardiac hypertrophy and heart failure, a shift from fatty acid metabolism to glucose metabolism, resulting in aggravated cardiac dysfunction. This review analyzes the relationship among the metabolism of different substrates in pathological cardiac remodeling. Based on these metabolic changes, we summarize the pharmacological agents, and raise new drug development strategies from the perspective of metabolic regulation, leading to an improved prognosis and treatment of patients with cardiac remodeling diseases.

  • 心血管疾病严重威胁人类健康,其中心脏重塑在心血管疾病中扮演重要角色。心脏重塑包括生理性重塑和病理性重塑。生理性重塑主要包括生长、 运动和妊娠时期的心脏改变,是对外部改变的有益适应。病理性重塑是炎症、缺血(再灌注)、生物应力、神经体液过度激活和压力超负荷等病理刺激导致心脏结构(体积、重量、形状) 和功能改变的过程[1]。病理性心脏重塑与纤维化、炎症以及细胞功能异常(例如异常的细胞相互作用、氧化应激、 内质网应激,自噬、信号通路受损)有关[2]。病理性心脏重塑是导致心功能恶化的重要病理过程,其作用越来越受到重视。

  • 代谢是生物体利用物质和能量进行生长、发育、维持其稳态的过程。心脏是代谢研究的重要器官,心脏重塑过程中代谢模式改变,影响心脏的结构和功能。生理状态下,胎儿心脏发育时期,子宫的低氧环境、心脏受限的可利用底物、低丰度的线粒体、低水平的脂肪酸氧化能力以及低循环负荷导致胎儿心脏的发育主要依靠糖酵解获取能量[3]。这种特定的代谢模式和发育程序使胎儿心脏具有维持心肌组织再生的能力。新生儿时期随着心脏发育, 心脏代谢从糖酵解转变为氧化磷酸化[3]。成年人正常心脏中95%的三磷酸腺苷(Adenosine Triphosphate,ATP) 来自氧化磷酸化,其余5%主要来自糖酵解中的底物水平磷酸化。为满足心脏的能量需求,多种代谢底物相互补充,包括脂肪酸、葡萄糖、氨基酸、乳酸、酮体、乙酸等[4, 5]。病理性心脏重塑时心脏代谢改变,心肌从脂肪酸为主的代谢特征转变为葡萄糖为主的代谢特征,心脏结构和功能发生异常。本文综述了病理性心脏重塑中的代谢改变,并分析了潜在的代谢干预靶点。

  • 1 代谢在病理性心脏重塑中的改变

  • 多种原因会引起心脏病理性重塑,包括压力超负荷,容量超负荷,心肌梗死,代谢性疾病等[5]。 不同原因引起的重塑病理机制不同,代谢改变也有差别[6, 7]。本文主要探讨压力超负荷导致心脏重塑的代谢改变。

  • 1.1 脂肪酸代谢

  • 在病理性心脏肥大或心力衰竭的病人中,由于疾病严重程度和病因的差异,心脏脂肪酸代谢如何改变未完全阐明[8-10]。一般共识认为,在病理性重塑中,心脏表现为胎儿时期的代谢特征,从脂肪酸代谢为主转变为葡萄糖代谢为主。临床研究提示, 心力衰竭过程中脂肪酸作为能量底物利用减少,葡萄糖的利用增加[8]。使用放射性标记示踪剂直接测量脂肪酸氧化水平,发现扩张型心肌病患者相比于对照组明显降低[8]。但这种代谢重塑的具体机制尚存争议[11]。一种假设认为病理状态下代谢底物偏好的改变保护衰竭的心脏免受进一步不可逆的结构和功能损害[12]。但是也有研究提示,抑制脂肪酸代谢也会加速心脏重塑的病理过程[13]

  • 1.2 葡萄糖代谢

  • 在心脏肥大和心力衰竭的过程中葡萄糖摄取会发生改变[14, 15]。尽管在压力超负荷引起的心脏肥大和心力衰竭早期胰岛素反应性降低[16],但是多种模型显示葡萄糖吸收和糖酵解速率增加[14]。在压力超负荷的情况下,心肌细胞特异性过表达葡萄糖转运体1(Glucose Transporter 1,GLUT1)可防止左心室扩张和心力衰竭[17],短期过表达GLUT1可减轻线粒体功能障碍和心脏纤维化,但是可能通过影响Ca2+ 代谢导致心脏收缩功能受损[18]。葡萄糖转运体4(Glucose Transporter 4,GLUT4)缺失的小鼠在基线情况下呈现正常的心脏功能,当给予压力超负荷刺激时,表现出更严重的收缩功能障碍[19]。这些结果表明,胰岛素依赖性葡萄糖摄取敏感性的降低是病理性的,增加心脏中葡萄糖的利用率可以抑制心脏肥大并改善心脏功能障碍。

  • 糖酵解中己糖激酶2(Hexokinase-2,HK2)代谢产生6-磷酸葡萄糖(Glucose-6-Phosphate,G-6-P), 通过增加磷酸戊糖途径(Pentose Phosphate Pathway,PPP)活性和还原型烟酰胺腺嘌呤二核苷酸磷酸(Reduced Nicotinamide Adenine Dinucleotide Phosphate,NADPH)含量减轻心脏肥大[20]。磷酸果糖激酶(Phosphofructokinase,PFK)活性的变化也可以调节心肌细胞辅助生物合成途径的活性,影响心脏重塑过程。在大鼠压力超负荷导致的心脏肥大中,PFK的表达升高,持续激活PFK2 中激酶活性提高2,6二磷酸果糖(Fructose-2,6-Bisphosphate, F-2,6-BP)水平,虽然促进糖酵解但却会加重心脏肥大和纤维化[21]。同样有研究表明在压力负荷模型下过表达PFK2中磷酸酶,减少F-2,6-BP,会加剧心脏的功能紊乱和纤维化[22],不同的结果可能来源于疾病模型、干预时间以及研究方法的差异。丙酮酸激酶(Pyruvate Kinase,PK) 也是糖酵解过程的关键酶之一,在心力衰竭的心脏中,丙酮酸激酶M2(Pyruvate Kinase M2,PKM2) 的表达明显升高[23],降低了PKM整体活性,促进PKM上游转向合成代谢分支途径(如丝氨酸途径和磷酸戊糖途径),积累合成代谢的中间代谢物,为心脏重塑提供原料[5]

  • 葡萄糖的其他代谢途径包括磷酸戊糖途径(PPP)、 氨基己糖生物合成途径(Hexosamine Biosynthesis Pathway,HBP)、甘油脂质代谢通路(Glycerolipid Pathway,GLP)和丝氨酸合成通路(Serine Biosynthesis Pathway,SBP),他们对病理性心脏重塑也有重要作用。PPP主要通过调节6-磷酸葡萄糖脱氢酶的活性来完成,该酶将6-磷酸葡萄糖和烟酰胺腺嘌呤二核苷酸磷酸(Nicotinamide Adenine Dinucleotide Phosphate,NADP+) 转化为6-磷酸葡萄糖酸内酯和NADPH[24],维持心肌细胞的正常的氧化还原状态和收缩功能,并且减轻缺血再灌注损伤。 但是它还会促进NADPH氧化酶产生超氧化物,加重心力衰竭。HBP代谢通路可以产生尿苷二磷酸N-乙酰基葡萄糖胺(Uridine Diphosphate N-acetylglucosamine,UDP-GlcNAc),进一步形成N-,O-糖基化蛋白。研究表明,心力衰竭时O-糖基化蛋白水平升高[25]。研究发现GLP和SBP等3-碳中间代谢物可能通过影响糖酵解和氨基酸代谢影响病理重塑[26],但具体机制仍然需要进一步研究。

  • 1.3 氨基酸代谢

  • 文献表明心脏组织内BCAA(支链氨基酸:亮氨酸、异亮氨酸和缬氨酸) 的升高会损害心脏功能,给予大鼠离体心脏灌流亮氨酸和异亮氨酸会导致心脏收缩功能障碍[27]。过量的BCAA及其代谢产物会抑制 α-酮戊二酸和丙酮酸脱氢酶的活性以及线粒体的呼吸作用。小鼠中敲除蛋白磷酸酶2Cm抑制BCAA的分解代谢,引起心脏进行性功能障碍。压力超负荷模型下,心脏功能紊乱,而给予支链 α-酮酸脱氢酶(Branched-chain α-Ketoacid Dehydrogenase,BCKD)激酶抑制剂可以促进BCAA的分解,改善心脏功能[28]

  • 2 靶向代谢治疗病理性心脏重塑

  • 近年来,通过干预代谢治疗心脏重塑引起越来越多的关注。病理性心脏重塑过程中底物代谢的改变,是疾病导致的结果还是机体的代偿性保护尚存争议。最初的观点认为,心脏重塑过程中底物代谢模式的转变是对正常心脏代谢的扰动。因此,治疗目标是纠正这种底物偏好的转变。通过外源性激活氧化物酶体增殖物激活受体(Peroxisome Proliferators Activated Receptors,PPAR) 促进心脏脂肪酸氧化,在不同的心脏肥大和心力衰竭模型中研究结果并不一致,包括有益[29]、无效[30] 甚至有害[31]。另一方面,脂肪酸的利用与活性氧(Reactive Oxygen Species,ROS) 的增加有关,ROS的增加会导致心脏损害[32]。在低氧水平下,脂肪酸代谢产生ATP效率较低。因此,直接或间接抑制脂肪酸氧化、促进葡萄糖利用也是病理性心脏重塑的代谢干预策略[33]。本文介绍了心脏肥大和心力衰竭中代谢干预靶点的相关研究。

  • 2.1 减少血浆游离脂肪酸

  • 血浆游离脂肪酸过多会抑制心肌摄取葡萄糖, 促进胰岛素抵抗的发生,促进ROS的形成,加剧心肌功能异常。心脏脂肪酸氧化能力下降可能导致长链脂肪酰基中间代谢物和甘油三酯的积累,引起脂毒性并加速心脏重塑的病理进展[34]。临床试验中发现烟酸及其衍生物可以通过降低循环中游离脂肪酸水平从而抑制心肌组织脂肪酸氧化水平[35]。阿昔莫司(Acipimox) 是一种烟酸衍生物,可以抑制脂肪分解,降低血浆游离脂肪酸[36, 37]。采用Acipimox治疗缺血性心衰患者28 天的临床试验发现,尽管血浆脂肪酸水平显著降低,葡萄糖利用增加,但未观察到心脏功能受益[37]。一种可能原因是,尽管增加了葡萄糖的摄取,但并不足以补偿脂肪酸作为底物的降低;另一种可能原因是,血浆游离脂肪酸急剧下降后,丙酮酸脱氢酶(Pyruvate Dehydrogenase, PDH) 的活性并没有被迅速上调。因此,尽管检测到葡萄糖摄入增加,但是心脏只是“耗尽了燃料”, 脂肪酸氧化的减少并没有伴随葡萄糖代谢的增加。 现有证据表明,通过抑制脂肪组织的分解来降低血浆脂肪酸水平并不能明显改善心衰患者的心脏功能。

  • 2.2 减少线粒体游离脂肪酸摄取

  • 肉碱酰基转移酶(Carnitine Palmitoyltransferase,CPT) 作为介导线粒体摄取脂肪酸的限速酶, 是抑制心肌脂肪酸 β 氧化的重要靶点。比较成熟的CPT1抑制剂,包括依托莫昔(Etomoxir)和哌己昔林(Perhexiline)[38]。Etomoxir是CPT1不可逆抑制剂,通过抑制脂肪酸进入线粒体,增加葡萄糖代谢,改善压力超负荷模型大鼠的心脏功能。在心脏肥大的情况下,Etomoxir通过提高肌浆网钙摄取速率可以延缓心力衰竭[39]。临床试验中,给予Etomoxir(每天80 mg,持续3个月)后,纽约心脏病协会(New York Heart Association,NYHA)心功能分级Ⅱ类患者的左心室射血分数、运动时的心输出量和临床状况均有改善[40]。但由于Etomoxir治疗的患者肝转氨酶水平明显升高,导致该多中心双盲临床试验被提前终止[41]。Perhexiline最初在20世纪70年代作为抗心绞痛药,最近临床试验发现短期Perhexiline干预可以将磷酸肌酸/三磷酸腺苷比值提高30%, 改善心脏能量代谢,改善NYHA的功能分级,但是并未看到左心室射血分数的改变[42]。由于CPT1抑制导致的肝功能改变和神经病变,导致其使用率下降。进一步研究发现将Perhexiline的血浆浓度保持在0.15~0.6 mg/L之间,可以抑制心脏CPT1而不抑制其肝脏同工酶的活性,有效改善慢性心力衰竭, 改善左心室射血分数和最大摄氧量,并改善整体心脏能量[43]

  • 丙二酰辅酶A是脂肪酸氧化的关键调节剂,可抑制CPT1并减少线粒体对脂肪酸的摄取。通过抑制丙二酰辅酶A脱羧酶(Malonyl-CoA Decarboxylase, MCD) 可增加心肌丙二酰辅酶A水平[44]。小鼠中敲除MCD可以减轻缺血再灌注损伤并减小梗死面积,这与丙二酰辅酶A水平的增加、脂肪酸氧化降低和葡萄糖代谢增强有关[45]。通过抑制MCD提高心脏产能效率,逆转心衰大鼠的心脏功能障碍[46]。 在药理上,MCD的抑制剂可以增加丙二酰辅酶A的含量,随后降低线粒体脂肪酸的摄取和氧化,改善心脏代谢[44]。但是在对MCD抑制剂进行临床研究之前,在大动物模型中进行疗效和安全性实验至关重要。

  • 2.3 部分抑制线粒体脂肪酸氧化

  • 直接抑制脂肪酸氧化的酶可以抑制线粒体脂肪酸氧化。研究中开发了多种脂肪酸氧化抑制剂,改善缺血性心脏病和心力衰竭。曲美他嗪(Trimetazidine) 是部分脂肪酸氧化抑制剂,可竞争性地抑制长链3-酮酰基-CoA硫解酶(3-Ketoacyl-CoA Thiolase,KAT),抑制脂肪酸氧化,提高葡萄糖代谢[47]。 在临床试验中可提高心力衰竭患者的NYHA功能等级、左心室舒张末期容积和射血分数。动物研究发现Trimetazidine可以通过激活AMPK和PPARα 调节酮体代谢,改善异丙肾上腺素所致的大鼠心肌代谢重塑[48]。在慢性心衰患者中额外使用Trimetazidine可以降低心源性住院率,改善临床症状[49]。 但是一项3 个月的临床试验中Trimetazidine并没有提高肥厚性心肌病患者的运动能力[50]。这可能反映了与CPT1 抑制剂相比,Trimetazidine对脂肪酸氧化的抑制作用较弱,或者3个月的持续治疗时间不足以改善症状。雷诺嗪(Ranolazine) 是另一个部分脂肪酸β-氧化抑制剂,可相应地增加葡萄糖代谢和PDH活性[51]。除了抑制脂肪酸 β-氧化外,Ranolazine能抑制钠电流,通过恢复Na+ 和Ca2+ 的稳态, 抑制下游的信号通路和内质网应激,改善压力超负荷引起的心脏肥大和功能紊乱[52]。总体来说,Ranolazine可能通过同时抑制Na+ 电流和脂肪酸氧化改善心脏功能。

  • 2.4 促进葡萄糖代谢

  • 对于心脏重塑,抑制心脏脂肪酸氧化会导致心脏组织中甘油三酯和其他脂质(包括甘油二酯、游离脂肪酸和神经酰胺等) 的蓄积,导致脂毒性[53]。 脂毒性会进一步激活心脏氧化应激和心肌细胞凋亡,加重心脏纤维化等病理改变,最终导致心脏收缩和舒张功能障碍[53]。因此直接增加心肌葡萄糖代谢作为改善心脏能量代谢的途径,可以部分避免心脏脂质堆积导致的脂毒性。二氯乙酸(Dichloroacetic Acid,DCA)可通过激活PDH复合物增强葡萄糖代谢,同时激活PPP通路并降低氧化应激损伤[54]。对于缺血再灌注导致的心脏肥大,DCA刺激葡萄糖代谢,抑制心脏肥大并改善心脏功能。在一项小型临床试验中,给予冠状动脉病变的患者DCA静脉输注,二氯乙酸盐可提高心肌乳酸利用并改善左心室机械效率[55]。同时,DCA会改变乙酰辅酶A的产生, 促进组蛋白H3K9和H4的乙酰化,调控基因表达, 这些效应也可能会影响心脏功能[56]。但是DCA发挥抑制活性的有效剂量较高(25~100 mg/kg) 及外周运动神经毒性限制了它的进一步的临床应用,其他新型丙酮酸脱氢酶激酶(Pyruvate Dehydrogenase Kinase,PDK) 抑制剂也在不断研发[57]。新型抑制剂PS8 和PS10 可以改善葡萄糖耐量并减少肝脂肪变性,同时PS10 可以促进肥胖小鼠中心肌葡萄糖代谢,改善糖尿病心脏肥大[58]。尽管如此,这些PDK抑制剂是否可以应用于心脏衰竭患者的治疗仍然需要进一步临床试验的验证。

  • 3 总结和展望

  • 心脏的能量代谢,特别是脂肪酸氧化和葡萄糖代谢,是高度精密的调控过程。心脏肥大和心力衰竭患者发生病理性心脏重塑和代谢模式改变。代谢的复杂性导致很难区分代谢重塑是疾病导致的结果还是机体的代偿性保护,病理性心脏重塑的不同阶段,其基因表达模式和代谢特征也不相同[59]。同时由于疾病病因、严重程度、检测方法和研究对象的异质性,导致不同的研究呈现相异的结果。病理性心脏重塑代谢改变研究将采用多层面多组学, 基于疾病进程进行连续动态、同步分析心脏基因表达模式和代谢特征,理解生理和病理条件下的代谢改变及其机制,为病理性心脏重塑的代谢干预提供新策略。

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