Chinese Journal of Tissue Engineering Research ›› 2021, Vol. 25 ›› Issue (35): 5729-5734.doi: 10.12307/2021.307
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Zhang Qunhui1, 2, 3, Li Yimei4, Zhang Dejun1, 2, 3
Received:
2020-11-05
Revised:
2020-11-06
Accepted:
2020-12-14
Online:
2021-12-18
Published:
2021-08-06
Contact:
Zhang Dejun, MD, Professor, Doctoral supervisor, Research Center for High Altitude Medicine, Medical College of Qinghai University, Xining 810001, Qinghai Province, China; College of Ecology and Environmental Engineering, Qinghai University, Xining 810016, Qinghai Province, China
About author:
Zhang Qunhui, MD candidate, Physician, Research Center for High Altitude Medicine, Medical College of Qinghai University, Xining 810001, Qinghai Province, China; College of Ecology and Environmental Engineering, Qinghai University, Xining 810016, Qinghai Province, China
Supported by:
CLC Number:
Zhang Qunhui, Li Yimei, Zhang Dejun. Hypoxia-inducible factor and coronary heart disease: antagonism and protection[J]. Chinese Journal of Tissue Engineering Research, 2021, 25(35): 5729-5734.
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2.1 HIF与冠心病靶基因 HIF作为重要的转录调节因子,调控多种参与冠心病发病机制的低氧反应基因。HIF-1和HIF-2对调控冠心病的靶点基因既有共性,也有个性。HIF-1促进糖酵解途径中磷酸甘油酸激酶基因和乳酸脱氢酶A基因的表达,而HIF-2促进Oct-4基因和TGF-α基因的表达[6]。HIF-1和HIF-2共同编码血管内皮生长因子α和葡萄糖转运体1基因[6]。当心肌发生氧化应激时,HIF-1诱导PDK1、PDK3、BNIP3和BNIP3L等基因高表达,从而减少活性氧的生成。此外,HIF-1高表达进一步促进了血管内皮生长因子、重组人血管生成素1 、重组人血管生成素2、前列腺素F、干细胞因子和基质细胞衍生因子等血管生成相关基因表达,从而形成侧支血管,进而改善缺血和缺氧[7]。美国一项研究发现冠状动脉狭窄患者冠脉侧支循环的形成与HIF-1α等位基因(P582S)相关[8]。美国另一项研究发现HIF-1α基因多态性与心绞痛的发生相关[9]。HUANG等[10]敲除心肌梗死模型鼠的PDH和FIH基因后,发现HIF-1表达增加,心脏内血管显著增加,心功能得以改善。CZIBIK等[11]对缺血灌注再损伤模型小鼠进行除心肌之外的组织中注射编码HIF-1α的DNA质粒,发现外源性HIF-1α高表达也能发挥抗心肌缺血再灌注损伤的作用。LI等[12]对心肌缺血再灌注损伤模型鼠进行缺血后处理,发现体内高表达HIF-1α和iNOS基因,心肌损伤面积减少,caspase-3活性降低。 2.2 HIF与冠心病代谢 心肌细胞对低氧适应的关键在于使氧化磷酸化的代谢途径转变为无氧酵解途径。HIF-1α的转录失活和心肌细胞的能量代谢障碍是心肌细胞损伤的关键环节。HIF-1α活化时,葡萄糖的有氧氧化过程受阻,糖酵解代谢增强,这导致三磷酸腺苷生成减少,心脏无法获取足够能量而发生功能障碍;心肌细胞的脂肪不断蓄积也导致心脏收缩障碍[13]。此时,功能损伤的线粒体无法正常供给三磷酸腺苷,导致心肌细胞发生水肿、缺血和坏死[14-16]。氧气的供需失衡是触发HIF-1α变化的重要因素,表现为葡萄糖摄取和糖酵解增加[17]。王雪梅等[18]发现HIF-1α在糖尿病心肌缺血再灌注损伤中通过提高PGC-1α的表达,提高线粒体的能量代谢水平,降低心肌的氧化应激损伤和凋亡。 2.3 HIF调控冠心病的分子机制 2.3.1 血管生成机制 促进心肌血管生成是治疗冠心病的创新治疗方法之一。血管生成指的是存活的毛细血管发育成血管。该过程受多种调控因子和信号分子的作用,HIF-1α通过促进一系列低氧反应基因来调节血管生成。SONG等[19]根据心脏血管生成作为一种新型心肌梗死治疗方案的想法,采用运动干预SD大鼠进行体内实验,在体外通过HIF-1α激动剂和抑制剂干预人脐静脉内皮细胞来明确心肌梗死病理生理过程中HIF-1α和miR-126对心脏保护的效果,其中体内实验发现运动训练可通过提高左心室收缩压和降低左心室舒张末期压来改善心功能,促进心脏血管生成,上调HIF-1α蛋白表达,且该效应可由HIF-1α抑制剂(2-methoxyestradiol,2-ME)进行阻断;而体外实验采用HIF-1α激动剂和HIF-1α抑制剂(2-ME),miR-126过表达和沉默来明确HIF-1α对miR-126表达的效应,发现miR-126模拟组PIK3R2和SPRED1蛋白表达显著减少,p-PI3K/PI3K,p-AKT/AKT和p-eNOS/eNOS表达显著增加,Raf-1蛋白和p-ERK/ERK表达显著增加。由此可见,转录调节因子HIF-1α高表达促进miR-126转录和翻译,并通过PI3K/AKT/eNOS和MAPK信号通路来诱导血管生成,进而保护心脏,但该研究的局限在于未探讨心肌梗死相关的炎症、凋亡和氧化应激等机制。 间充质干细胞分泌的外泌体具有促进血管生成的作用。SUN等[20]探讨HIF-1α修饰的间充质干细胞外泌体对心脏保护和血管生成的效果,其中体外实验发现低氧导致人脐静脉内皮细胞的血管生成作用受损,而外泌体的应用促进了血管生成,进一步研究发现HIF-1α修饰的外泌体一方面上调血管内皮生长因子、血管紧张素Ⅰ和血小板衍生因子基因的表达,另一方面提高人脐静脉内皮细胞的增殖和迁移能力。体内实验显示,外泌体以及经HIF-1α修饰的外泌体均可通过提高左心室射血分数和减少心室重构来改善心功能;病理形态学观察到经HIF-1α修饰的外泌体可显著减少梗死心肌的纤维化,梗死区血管生成明显。 既往研究显示许多细胞表达碱性成纤维细胞因子,而该因子具有促进细胞存活、迁移和增殖的能力[21]。因此,YAO等[22]围绕碱性成纤维细胞因子是否可作为心肌梗死药物的观点,对心肌梗死模型SD大鼠进行尾静脉注射碱性成纤维生长因子来干预,体内实验发现模型鼠的左心室功能得到改善和左心室舒张末期直径减小;而体外实验发现HIF-1α和VEGF的mRNA表达显著增加,该研究存在以下不足:未定性/定量分析HIF-1α和VEGF的mRNA表达量,从而无法证实碱性成纤维生长因子诱导HIF-1α和VEGF的mRNA表达效果。类似地,RAO等[23]为进一步明确碱性成纤维细胞因子干预C57BL/6J心肌梗死模型小鼠血管生成的机制,体内实验从功能学来看,与对照组相比,干预组左心室射血分数明显增加;从病理形态学来看,碱性成纤维细胞因子干预后梗死区的纤维化显著减少。采用腹腔注射碱性成纤维细胞因子来干预模型小鼠,Tunel分析发现碱性成纤维细胞因子对抗心肌微血管内皮细胞凋亡是通过上调HIF-1α表达实现;免疫组化结果显示碱性成纤维细胞因子诱导梗死区血管新生,为进一步明确HIF-1α在心肌微血管内皮细胞中发挥血管生成的作用机制,免疫印迹结果表明碱性成纤维细胞因子通过AKT/HIF1α/VEGF信号通路来诱导血管生成,碱性成纤维细胞生长因子在预防心肌梗死方面具有潜在的临床应用价值。 LAKKISTO 等[24]研究发现血红素氧合酶1和一氧化碳在心肌梗死后心脏再生中发挥不同的作用,其中一氧化碳通过激活c-kit+祖细胞和HIF-1α、基质细胞衍生因子1α和血管内皮生长因子表达,促进血管新生和心肌分化,而血红素氧合酶1仅通过促进HIF-1α和基质细胞衍生因子1α的表达来保护梗死心肌。由此可见,血红素氧合酶1和一氧化碳是促进心肌再生的内源性化学成分。 雄激素睾酮在心血管疾病中的作用一直存在争议。既往临床研究提示严重冠心病男性患者的冠状动脉侧支循环丰富,基础研究提示雄激素具有调节内皮功能、改善冠脉血流量、抗心绞痛和抗动脉粥样硬化的作用。因此,CHEN等[25]利用急性心肌梗死去势模型大鼠研究睾酮替代疗法对心肌血管生成的影响,发现睾酮可以增加CD34+细胞在缺血心肌中的动员和募集,从而促进心肌梗死后心肌血管的新生,这种心肌保护效应与睾酮诱导HIF-1α、基质细胞衍生因子1α和血管内皮生长因子高表达相关。 以脯氨酸羟化酶抑制剂为代表的化学药物促进心肌梗死后血管生成发挥重要的作用。脯氨酸羟化酶作为氧传感器,是生理和病理状态下调控HIF的重要靶点。当脯氨酸羟化酶活性下降时,会触发HIF-1α表达的一系列信号,在糖酵解、红细胞生成、凋亡和血管生成等方面发挥重要的生物学作用。因此,ORIOWO等[26]为阐明脯氨酸羟化酶3对心肌缺血再灌注损伤的保护机制而开展研究。体外实验将人脐静脉内皮细胞的脯氨酸羟化酶3基因进行沉默,毛细血管样结构显著增加,细胞凋亡减少。类似地,将脯氨酸羟化酶3基因敲除,心肌梗死后毛细血管和小动脉密度增加。体内实验将脯氨酸羟化酶3基因敲除,发现血管内皮生长因子、血管紧张素1和Bcl-2表达增加,左心室射血分数增加,纤维化减少,心功能得到显著改善。 以中医药为代表的传统医药是中华民族的瑰宝,DU 等[27]围绕麝香酮能否促进心肌梗死模型鼠血管生成及其内在机制开展研究,发现麝香酮干预C57BL模型小鼠4周后心脏射血功能和收缩功能得到显著改善,心肌纤维化减少,血管生成增加;免疫印迹实验结果显示麝香酮上调HIF-1α、VEGFA和p-AKT表达,该研究首次证明麝香酮基于HIF-1α/VEGFA信号通路来促进血管生成,从而达到干预心肌梗死的效果。 2.3.2 凋亡机制 当心肌细胞内质网发生严重应激时, 78 kD葡萄糖调节蛋白上调,促进心肌细胞凋亡[28]。DATTA CHAUDHURI等[29]为明确不同低氧程度和持续时间时HIF-1α调控心肌细胞凋亡的机制而开展体内外实验,结果发现活性氧维持HIF-1α稳定并诱导心肌细胞发生凋亡,而一氧化氮虽然可维持HIF-1α稳定性,但阻断凋亡发生,具体机制如下:持续中度低氧时诱导型一氧化氮合酶促进NF-κB活性依赖性的一氧化氮生成,高浓度的一氧化氮维持HIF-1α稳定性,而较低浓度的活性氧无法活化ERK1/2,而高浓度的活性氧不仅维持HIF-1α稳定性,还可活化ERK1/2。ERK1/2的激活可使HIF-1α发生磷酸化,再进入到细胞核内不断积累,进而触发bnip3介导的细胞凋亡,细胞核内HIF-1α磷酸化减少将下调bnip3介导的细胞凋亡,而细胞质中的HIF-1α对bnip3无调控作用。此外,IRE-1与HSP90结合诱导Caspase-12的表达,而细胞质中的HIF-1α阻断IRE-1与HSP90的结合,而使Caspase-12表达降低。SUN等[30]也采用miRNA在体内外干预缺氧心肌细胞和动物模型,qRT-PCR检测发现低氧心肌细胞高表达miR-145。为进一步研究miR-145变化原因,该研究采用外源基因表达和基因沉默技术,发现HIF-1α是上述环节的重要调节因子。为明确miR-145变化带来的生物学效应,通过模拟miR-145和阻断miR-145进行实验,结果发现常氧下miR-145的表达水平与H9c2心肌细胞的活力和迁移能力呈正相关,而低氧下miR-145通过抑制缺氧H9c2心肌细胞的凋亡来保护心肌细胞。为深入探讨低氧下miR-145对H9c2心肌细胞的保护机制,蛋白印迹结果显示SGK1和PI3K/AKT信号通路参与miR-145保护H9c2心肌细胞,同样的结果在体内实验也得到了相同的验证,因此,miR-145为急性心肌梗死的早期诊断提供了可能。 促红细胞生成素作为一种糖蛋白激素,在调节红细胞生成和保护心脏方面发挥重要的作用,但具体作用机制不详。既往研究显示促红细胞生成素通过PI3K-Akt信号通路来抑制细胞凋亡,减少梗死面积,从而保护心脏,但这种效应是否随着促红细胞生成素浓度的变化而变化?GUVEN BAGLA等[31]发现促红细胞生成素干预心肌缺血模型大鼠后心肌细胞凋亡发生减少;心肌梗死边缘区HIF-1α和caspase-3表达增加;心肌梗死早期,促红细胞生成素诱导新生的血管并无心肌保护作用;促红细胞生成素对心脏的保护作用独立于促红细胞生成素及其受体的活性,且通过其受体发挥心脏保护作用;与标准剂量促红细胞生成素干预相比,高剂量促红细胞生成素并不能增加获益,亟待开展更多大型研究来明确急性心肌梗死和不同剂量促红细胞生成素的心脏保护作用关系。 YU等[32]探究急性心肌梗死时黄芪甲苷抗心肌损伤的作用及其机制,体内实验发现黄芪甲苷不仅在宏观角度上可减轻心肌梗死大鼠的心脏扩张和减小梗死面积,还能在微观上减少浸润的炎症细胞、坏死心肌细胞和胶原纤维。为探讨其内在机制,在转录组水平黄芪甲苷对心肌梗死模型鼠进行干预时,HIF-1α、Notch1和Jagged1的mRNA表达增加;蛋白印迹结果显示,与模型组相比,HIF-1α、Notch1和Jagged1的蛋白表达均增加。由此可见,黄芪甲苷通过上调Notch1/Jagged1信号通路来抑制缺血损伤的心肌细胞凋亡,但该研究未考虑以下问题:心肌缺血是一个动态过程,未探讨HIF-1α、Notch1和Jagged1动态表达,以及未深入探讨HIF-1α与Notch1/Jagged1的调控机制[32]。 2.3.3 炎症机制 炎症是心肌梗死的重要机制[33]。当心肌梗死发生时,炎症反应迅速发生并释放大量的炎症细胞和炎症因子来清除坏死的心肌细胞。心肌梗死急性期会加剧心肌细胞损害、心室重构和心功能障碍。因此,LAI等[34]围绕降香黄檀的提取物阔叶黄檀酚是否通过减少心肌细胞的炎症来改善心肌缺血这一问题开展研究,发现阔叶黄檀酚能显著降低心肌酶水平,提高左心室射血分数,且干预的最佳剂量为100 mg/kg,形态学观察可见心肌梗死面积减小,巨噬细胞浸润减少,心肌纤维化减少,研究发现阔叶黄檀酚对心肌梗死的保护是基于HIF-1α/NF-κB/IL-6信号转导通路缓解炎症来实现的,但该研究存在以下局限:虽然观察到巨噬细胞的明显变化,但未明确阔叶黄檀酚对心肌梗死和巨噬细胞亚型的影响;调节HIF-1α的信号通路很多,该研究仅观察到HIF-1α的下降,但并未对具体机制展开研究。YU等[35]针对阿托伐他汀钙片联合常规治疗对心肌梗死模型Wistar大鼠HIF-1和血管内皮生长因子的影响进行探究,结果发现阿托伐他汀钙片联合常规治疗可显著增加HIF-1和血管内皮生长因子的浓度,且两者浓度的增加与治疗时间呈正相关,与左心室收缩期内径和左心室舒张期内径呈负相关,与左心室射血分数和左心室短轴缩短率呈正相关,从而保护心肌。换言之,HIF-1和血管内皮生长因子的浓度可用于判断心肌功能的恢复。因此,该研究推测心肌梗死发生时HIF-1α/VEGF信号通路激活,促进心肌细胞增殖,同时阿托伐他汀通过降低炎症级联反应和抗凝血酶活性来稳定冠状动脉粥样斑块,延缓心肌重塑和减轻左心功能损害,但该研究的局限在于未深入探讨HIF-1α和血管内皮生长因子在心肌梗死中的具体机制。既往研究表明白细胞计数增加导致心肌梗死后左心室发生重塑进而发生扩大,阻断趋化因子有利于促进心肌梗死后心肌愈合。DONG等[36]为明确白细胞、趋化因子在心肌梗死时发挥的调控机制而开展研究,发现白细胞HIF-1α的表达可以抑制中性粒细胞和单核细胞迁移,进而导致炎症部位募集的白细胞减少,改善心脏重塑和心功能。HIF-1α下调导致细胞因子受体的表达减少,如CCR-1、CCR-2、CCR-4,抑制白细胞迁移。 2.3.4 自噬机制 WANG等[37]围绕浒苔多糖在体内和体外干预心肌梗死并探讨其内在机制这一问题开展研究,体内实验发现浒苔多糖通过上调HIF-1α来保护人心脏微血管内皮细胞免于糖氧剥夺造成的损害,并抑制凋亡。为进一步探讨HIF-1α上调机制,采用MEK/ERK信号通路抑制剂(CH5126766)干预人心脏微血管内皮细胞缺血缺氧模型,发现MEK和p-ERK的表达减少,并呈现出剂量依赖效应。为进一步研究保护人心脏微血管内皮细胞免于糖氧剥夺损害的机制,发现浒苔多糖一方面上调HIF-1α的表达来抑制NF-κB信号通路,另一方面激活mTOR信号通路来抑制自噬的发生,通过上述两条通路提高细胞活力,促进细胞增殖,抑制细胞凋亡,减少细胞炎症。体外实验发现浒苔多糖通过上调HIF-1α的表达来保护心功能并减少梗死心肌范围。 2.3.5 纤维化机制 SUI等[38]探讨缬沙坦治疗心肌梗死模型SD大鼠的作用机制,体外实验发现低氧时心肌细胞表达的AngⅡ、TGF-β/Smad、HIF-1α和心肌纤维化显著升高。为明确这种变化的原因,采用缬沙坦阻断AT-1受体,发现TGF-β/Smad、HIF-1α和胶原的表达均减少,即低氧条件下AngⅡ通过AT-1受体促进TGF-β/Smad、HIF-1α和胶原的表达。为探讨心肌纤维化与TGF-β/Smad和HIF-1α的关系,发现TGF-β/Smad和HIF-1α协同参与心肌纤维化的发生。蛋白印迹结果显示缬沙坦抑制转化生长因子β、基质金属蛋白酶2和基质金属蛋白酶9等纤维化蛋白的表达,从而减少胶原纤维的生成,进而达到预防心肌纤维化进一步扩大的效果。体内实验发现缬沙坦通过提高左心室射血分数和左心室短轴缩短率来改善心功能。从病理形态学来看,缬沙坦通过阻断梗死心肌范围的进一步扩大,增加梗死区心肌的厚度和促进血管新生来改善心功能。"
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