

浏览全部资源
扫码关注微信
1.广州中医药大学 第二临床医学院,广州 510000
2.广东省中医药防治难治性慢病重点实验室,广州 510000
Received:23 March 2020,
Published Online:25 July 2020,
Published:20 December 2020
移动端阅览
谢延峥,马金,邹旭.PI3K/Akt信号通路串扰在心肌缺血再灌注损伤中的作用及中医药防治进展[J].中国实验方剂学杂志,2020,26(24):201-210.
XIE Yan-zheng,MA Jin,ZOU Xu.Effect of PI3K/Akt Signal Pathway Crosstalk in Myocardial Ischemia Reperfusion Injury and Prevention and Treatment with Traditional Chinese Medicine Therapy[J].Chinese Journal of Experimental Traditional Medical Formulae,2020,26(24):201-210.
谢延峥,马金,邹旭.PI3K/Akt信号通路串扰在心肌缺血再灌注损伤中的作用及中医药防治进展[J].中国实验方剂学杂志,2020,26(24):201-210. DOI: 10.13422/j.cnki.syfjx.20201872.
XIE Yan-zheng,MA Jin,ZOU Xu.Effect of PI3K/Akt Signal Pathway Crosstalk in Myocardial Ischemia Reperfusion Injury and Prevention and Treatment with Traditional Chinese Medicine Therapy[J].Chinese Journal of Experimental Traditional Medical Formulae,2020,26(24):201-210. DOI: 10.13422/j.cnki.syfjx.20201872.
心肌缺血再灌注损伤(MIRI)是指由于一些原因导致心肌细胞缺血性损伤,然而在恢复血液供应后心肌细胞损伤进一步加重,从而引发再灌注性心律失常、心肌顿抑、微循环障碍和血液无复流等现象,是临床治疗中亟待解决的问题。因此,探索如何改善MIRI具有重要的临床意义。磷脂酰肌醇3-激酶(PI3K)/蛋白激酶B(Akt)信号通路被认为是预防MIRI的重要级联信号通路,串扰在氧化应激、钙超载、自噬、炎症、内质网应激和线粒体障碍等多种机制中,并处于核心位点,与MIRI的严重程度密切相关。同时,中医药凭借其多靶点、多通路和毒副作用小的优势以及中医的辨证治疗、整体观念等特点,使其在防治MIRI方面有着独特的优势。大量研究已证实,该通路是众多中药复方、中药单体以及中药提取物常见的作用机制。因此,本文将阐述PI3K/Akt信号通路串扰在MIRI机制中的作用,重点对PI3K/Akt信号通路关键靶标与MIRI的关系进行综述,以便深刻理解其中错综复杂的关系,促进针对PI3K/Akt信号通路的新型药物的研发。最后总结中医药对该通路已有的研究成果,为MIRI的治疗及药物研发提供参考依据。
Myocardial ischemia-reperfusion injury (MIRI) was originated from the ischemic injury to myocardial cells due to some factors, and the injury will be aggravated after the blood supply recovery. MIRI will cause reperfusion arrhythmia, myocardial stagnation, microcirculation disorders or blood loss reflow, and become a key issue to be solved in the clinical treatment. Therefore, it is of important clinical significance to explore how to improve MIRI. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway has been regarded to be an important cascade signaling pathway to prevent MIRI, which is cross-talked in such mechanisms as oxidative stress, calcium overload, autophagy, inflammation, endoplasmic reticulum stress and mitochondrial dysfunction. This pathway is at the core site and closely related to the severity of MIRI. Meanwhile, traditional Chinese medicine(TCM) has its unique advantages in the prevention and treatment of MIRI, including multiple targets, multiple pathways, fewer toxic and side effect, as well as TCM characteristics of syndrome differentiation treatment and overall concept. A great number of studies have confirmed that this pathway is a common mechanism of action for most TCM compounds, TCM monomers and extracts. In this paper, we clarify the effect of PI3K/Akt signaling pathway crosstalk on the myocardial ischemia-reperfusion injury, with the focus on the relationship between the key targets of PI3K/Akt signaling pathway and MIRI. It will give great insights to the intricate relationship between them and promote the future development of new drugs targeting the PI3K/Akt signaling pathway. Finally, we also summarized the existing findings of TCM on PI3K/Akt pathway, which provides a reference for the treatment and drug development of MIRI.
胡盛寿 , 高润霖 , 刘力生 , 等 . 《中国心血管病报告2018》概要 [J]. 中国循环杂志 , 2019 , 34 ( 3 ): 209 - 220 .
ZHOU W J , LI J L , ZHOU Q M , et al . Ginsenoside Rb1 pretreatment attenuates myocardial ischemia by reducing calcium/calmodulin-dependent protein kinase II-medicated calcium release [J]. World J Tradit Chin Med , 2020 , 6 ( 3 ): 284 - 294 .
JENNINGS R B , SOMMERS H M , SMYTH G A , et al . Myocardial necrosis induced by temporary occlusion of a coronary artery in the dog [J]. Arch Pathol , 1960 , 70 : 68 - 78 .
THOMAS M , CAMICI G G , MAACK C , et al . Impact of oxidative stress on the heart and vasculature [J]. J Am Coll Cardiol , 2017 , 70 ( 2 ): 212 - 229 .
WALTERS A M , POTER J R G A , BROOKES P S . Mitochondria as a drug target in ischemic heart disease and cardiomyopathy [J]. Circ Res , 2012 , 111 ( 9 ): 1222 - 1236 .
MARCHANT D J , BOYD J H , LIN D C , et al . Inflammation in myocardial diseases [J]. Circ Res , 2012 , 110 ( 1 ): 126 - 144 .
辛高杰 , 付建华 , 李磊 , 等 . 中药调控自噬与缺血性心脏病关系的研究进展 [J]. 中国中药杂志 , 2020 , 45 ( 16 ): 3784 - 3789 .
YU H J , GUAN Q G , GUO L , et al . Gypenosides alleviate myocardial ischemia-reperfusion injury via attenuation of oxidative stress and preservation of mitochondrial function in rat heart [J]. Cell Stress Chaperon , 2016 , 21 ( 3 ): 429 - 437 .
FRUMAN D A , ROMMEL C . PI3K and cancer:Lessons,challenges and opportunities [J]. Nat Rev Drug Discov , 2014 , 13 ( 2 ): 140 - 156 .
吴丹 , 高耀 , 向欢 , 等 . PI3K/Akt信号通路在抑郁症及抗抑郁中药作用机制研究中的进展 [J]. 中草药 , 2019 , 50 ( 18 ): 4461 - 4469 .
潘晔 , 殷佳 , 蔡雪朦 , 等 . 基于PI3K/Akt信号通路探讨中医药治疗冠心病的研究进展 [J]. 中草药 , 2017 , 48 ( 19 ): 4100 - 4104 .
JEYAMOHAN S , MOORTHY R K , KANNAN M K , et al . Parthenolide induces apoptosis and autophagy through the suppression of PI3K/Akt signaling pathway in cervical cancer [J]. Biotechnol Lett , 2016 , 38 ( 8 ): 1251 - 1260 .
聂阳 , 丁立 , 黄海潮 , 等 . PI3K/Akt-eNOS信号通路在甘木通总黄酮后处理减轻大鼠心肌缺血再灌注损伤作用 [J]. 中国中药杂志 , 2018 , 43 ( 23 ): 4692 - 4697 .
BRAND C S , LIGHTHOUSE J K , TREMBLEY M A . Protective transcriptional mechanisms in cardiomyocytes and cardiac fibroblasts [J]. J Mol Cell Cardiol , 2019 , 132 : 1 - 12 .
XIN G , XU Y L , SHAN H , et al . SH2B1 protects cardiomyocytes from ischemia/ reperfusion injury via the activation of the PI3K/Akt pathway [J]. Int Immunopharmacol , 2020 , doi: 10.1016/j.intimp.2019.105910 http://dx.doi.org/10.1016/j.intimp.2019.105910 .
CUI Z H , ZHANG X J , SHANG H Q , et al . Glutamine protects myocardial ischemia-reperfusion injury in rats through the PI3K/Akt signaling pathway [J]. Eur Rev Med Pharmacol Sci , 2020 , 24 : 444 - 451 .
CHEN X , ZHABYEYEV P , AZAD A K , et al . Endothelial and cardiomyocyte PI3K β divergently regulate cardiac remodelling in response to ischaemic injury [J]. Cardiovasc Res , 2019 , 115 ( 8 ): 1343 - 1356 .
PHUKAN S , BABU V S , KANNOJI A , et al . GSK3beta:role in therapeutic landscape and development of modulators [J]. Br J Pharmacol , 2010 , 160 ( 1 ): 1 - 19 .
JUHASZOVA M , ZOROV D B , KIM S H , et al . Glycogen synthase kinase-3 β mediates convergence of protection signalling to inhibit the mitochondrial permeability transition pore [J]. J Clin Invest , 2004 , 113 ( 11 ): 1535 - 1549 .
车建鹏 , 晏浩 , 徐建军 . GSK-3 β 参与心肌缺血中细胞程序性死亡的研究进展 [J]. 广东医学 , 2012 , 33 ( 10 ): 1498 - 1501 .
WU N , ZHANG X W , BAO Y D , et al . Down-regulation of GAS5 ameliorates myocardial ischaemia/reperfusion injury via the miR-335/ROCK1/AKT/GSK-3 β axis [J]. J Cell Mol Med , 2019 , 23 ( 12 ): 8420 - 8431 .
JARAMILLO M C , ZHANG D D . The emerging role of the Nrf2-Keap1 signaling pathway in cancer [J]. Gene Dev , 2013 , 27 ( 20 ): 2179 - 2191 .
LI W , ZHENG S , HIGGINS M , et al . New monocyclic,bicyclic,and tricyclic ethynylcyanodienones as activators of the Keap1/Nrf2/ARE pathway and inhibitors of inducible nitric oxide synthase [J]. J Med Chem , 2015 , 58 ( 11 ): 4738 - 4748 .
YU A , ZHOU R H , XIA B Z , et al . NAMPT maintains mitochondria content via NRF2-PPARα/AMPKα pathway to promote cell survival under oxidative stress [J]. Cell Signal , 2014 , 13 ( 2 ): 140 - 156 .
VOMUND S , SCHAFER A , PARNHAM M J , et al . Nrf2,the master regulator of anti-oxidative responses [J]. Int J Mol Sci , 2017 , 18 ( 12 ): E2722 .
AOYAGI T , KUSAKARI Y , XIAO C Y , et al . Cardiac mTOR protects the heart against ischemia-reperfusion injury [J]. Am J Physiol-Heart C , 2012 , 303 ( 1 ): H75 - H85 .
GALLO S , SALA V , GATTI S , et al . Cellular and molecular mechanisms of HGF/Met in the cardiovascular system [J]. Clin Sci , 2015 , 129 ( 12 ): 1173 - 1193 .
SCIARRETTA S , FORTE M , FRATI G , et al . New insights into the role of mTOR signaling in the cardiovascular system [J]. Circ Res , 2018 , 122 ( 3 ): 489 - 505 .
COHEN M V , YANG X M , DOWNEY J M . Nitric oxide is a preconditioning mimetic and cardioprotectant and is the basis of many available infarct-sparing strategies [J]. Cardiovasc Res , 2006 , 70 ( 2 ): 231 - 239 .
ZHANG X , HUANG L F , HUA L H , et al . Resveratrol protects myocardial apoptosis induced by ischemia-reperfusion in rats with acute myocardial infarction via blocking P13K/Akt /e-NOS pathway [J]. Eur Rev Med Pharmaco , 2019 , 23 ( 4 ): 1789 - 1796 .
CROSS T G , SCHEEL-TOELLNER D , HENRIQUEZ N V , et al . Serine/threonine protein kinases and apoptosis [J]. Exp Cell Res , 2000 , 256 ( 1 ): 34 - 41 .
YING Z , XIE X , CHEN M , et al . Alpha-lipoic acid activates eNOS through activation of PI3-kinase/Akt signaling pathway [J]. Vascul Pharmacol , 2015 , 64 : 28 - 35 .
梁俊清 , 徐海波 , 陈小娟 , 等 . 通心络通过PI3K/Akt/HIF信号通路改善血管内皮细胞缺氧损伤 [J]. 中国病理生理杂志 , 2012 , 28 ( 5 ): 846 - 851 .
CHEN J , GRAHAM S H , ZHU R L , et al . Stress proteins and tolerance to focal cerebral ischemia [J]. J Cerebr Blood F Met , 1996 , 16 ( 4 ): 566 - 577 .
MCCAFFREY G , STAATZ W D , QUIGLEY C A . et al.Tight junctions contain oligomeric protein assembly critical for maintaining blood-brain barrier integrity in vivo [J]. J Neurochem , 2007 , 103 ( 6 ): 2540 - 2555 .
CAPECE D , VERZELLA D , DI F B . et al.NF- κ B and mitochondria cross paths in cancer:mitochondrial metabolism and beyond [J]. Semin Cell Dev Biol , 2020 , 98 : 118 - 128 .
SUN N , WANG H , WANG L . Protective effects of ghrelin against oxidative stress,inducible nitric oxide synthase and inflammation in a mouse model of myocardial ischemia/reperfusion injury via the HMGB1 and TLR4/NF- κ B pathway [J]. Mol Med Rep , 2016 , 14 ( 3 ): 2764 - 2770 .
王文艳 , 徐彤彤 , 曾文轩 , 等 . 瘦素经PI3K-Akt-NF- κ B通路对大鼠心肌缺血再灌注损伤的影响 [J]. 临床心血管病杂志 , 2015 , 31 ( 12 ): 1336 - 1339 .
赵桂峰 , 黄欣玮 , 吴丽玉 . 基于NF- κ B通路的参芍胶囊保护大鼠心肌缺血再灌注损伤的机制分析 [J]. 中国实验方剂学杂志 , 2017 , 23 ( 12 ): 145 - 150 .
OBSIL T , OBSILOVA V . Structural basis for DNA recognition by FOXO proteins [J]. Biochim Biophys Acta , 2011 , 1813 ( 11 ): 1946 - 1953 .
BROWNAWELL A M , KOPS G L , MACARA I G , et al . Inhibition of nuclear import by protein kinase B(Akt) regulates the subcellular distribution and activity of the forkhead transcription factor AFX [J]. Mol Cell Biol , 2001 , 21 ( 10 ): 3534 - 3546 .
MAMMUCARI C , MILAN G , ROMANELLO V , et al . FoxO3 controls autophagy in skeletal muscle in vivo [J]. Cell Metab , 2007 , 6 ( 6 ): 458 - 471 .
ZHAO J , BRAULT J J , SCHILD A , et al . FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells [J]. Cell Metab , 2007 , 6 ( 6 ): 472 - 483 .
BEGANDT D , GOOD M E , KELLER A S . et al.Pannexin channel and connexin hemichannel expression in vascular function and inflammation [J]. Bmc Cell Biol , 2017 , 18 ( 1 ): 2 .
郑涛 , 李奇 , 杨简 , 等 . 缝隙连接蛋白43与心肌缺血再灌注损伤的研究进展 [J]. 生命的化学 , 2019 , 39 ( 2 ): 284 - 288 .
BOENGLER K , SCHULZ R . Connexin 43 and mitochondria in cardiovascular health and disease [J]. Adv Exp Med Biol , 2017 , 982 : 227 - 246 .
SOLAN J L , LAMPE P D . Spatio-temporal regulation of connexin43 phosphorylation and gap junction dynamics [J]. Biochim Biophys Acta , 2018 , 1860 ( 1 ): 83 - 90 .
GADICHERLA A K , WANG N , BULIC M , et al . Mitochondrial Cx43 hemichannels contribute to mitochondrial calcium entry and cell death in the heart [J]. Basic Res Cardiol , 2017 , 112 ( 3 ): 27 .
田攀 , 马宏 . 缝隙连接蛋白43与心律失常的研究进展 [J]. 中国循证心血管医学杂志 , 2016 , 8 ( 02 ): 238 - 239 .
JUHASZOVA M , ZOROV D B , KIM S H , et al . Glycogen synthase kinase-3 β mediates convergence of protection signalling to inhibit the mitochondrial permeability transition pore [J]. J Clin Invest , 2004 , 113 ( 11 ): 1535 - 1549 .
ZHOU P , YANG X L , YANG D Z , et al . Integrin-linked kinase activation prevents ventricular arrhythmias induced by ischemia/reperfusion via inhibition of connexin 43 remodeling [J]. J Cardiovasc Transl Res , 2020 , doi: 10.1007/s12265-020-09979-2 http://dx.doi.org/10.1007/s12265-020-09979-2 .
LU Q , LI WD , LI Z G , et al . Effect of autophagy on cardiomyocyte membrane Cx43 acute remodeling in rats with ischemia-reperfusion [J]. Int J Clin Exp Pathol , 2019 , 12 ( 7 ): 2639 - 2645 .
BAO X Y , ZHENG Q , TONG Q , et al . Danshensu for myocardial ischemic injury:preclinical evidence and novel methodology of quality assessment tool [J]. Front Pharmacol , 2018 , doi: 10.3389/fphar.2018.01445 http://dx.doi.org/10.3389/fphar.2018.01445 .
ZHANG J L , ZHANG Q Q , LIU G , et al . Therapeutic potentials and mechanisms of the Chinese traditional medicine Danshensu [J], Eur J Pharmacol , 2019 , 864 : 172710 .
金云晔 , 翟昌林 , 沈震 , 等 . 丹参酮Ⅱ A 磺酸钠对大鼠缺血再灌注心肌细胞凋亡的影响 [J]. 中华中医药学刊 , 2014 , 32 ( 6 ): 1413 - 1415 , 1548 - 1549 .
LIU H Q , LIU W , QIU H L , et al . Salvianolic acid B protects against myocardial ischaemia-reperfusion injury in rats via inhibiting high mobility group box 1 protein expression through the PI3K/Akt signalling pathway [J]. Naunyn Schmiedebergs Arch Pharmacol , 2019 , doi: 10.1007/s00210-019-01755-7 http://dx.doi.org/10.1007/s00210-019-01755-7 .
LI W , WANG Y P , GAO L , et al . Resveratrol protects rabbit ventricular myocytes against oxidative stress-induced arrhythmogenic activity and Ca 2+ overload [J]. Acta Pharmaeol Sin , 2013 , 34 ( 9 ): 1164 - 1173 .
宋娟 , 王佳 , 李宝红 , 等 . PI3K/Akt信号通路在白藜芦醇抗大鼠缺血/再灌注性心律失常中的作用及机制 [J]. 中国应用生理学杂志 , 2017 , 33 ( 3 ): 239 - 243 .
CHONG E , CHANG S L , HSIAO Y W , et al . Resveratrol,a red wine antioxidant,reducesatrial fibrillation susceptibility in the failing heart by PI3K/AKT/eNOS signaling pathway activation [J]. Heart Rhythm , 2015 , 12 ( 5 ): 1046 - 1056 .
YU Y L , XING N , XU X D , et al . Tournefolic acid B,derived from Clinopodium chinense (Benth) Kuntze,protects against myocardial ischemia/reperfusion injury by inhibiting endoplasmic reticulum stress-regulated apoptosis via PI3K/Akt pathways [J]. Phytomedicine , 2019 , 52 : 178 - 186 .
WEI D J , XU H J , GAI X D , et al . Astragaloside IV alleviates myocardial ischemia-reperfusion injury in rats through regulating PI3K/Akt/GSK-3 β signaling pathways [J]. Acta Cir Bras , 2019 , doi: 10.1590/s0102-865020190070000008 http://dx.doi.org/10.1590/s0102-865020190070000008 .
ZHANG C , LIANG R G , GAN X W , et al . MicroRNA-384-5p/Beclin-1 as potential indicators for epigallocatechin gallate against cardiomyocytes ischemia reperfusion injury by inhibiting autophagy via PI3K/Akt pathway [J]. Drug Des Devel Ther , 2019 , 13 : 3607 - 3623 .
ZHOU H , HOU S , ZHEN L P . et al.Ginseng protects rodent hearts from acute myocardial ischemia-reperfusion injury through GR/ER-activated RISK pathway in an endothelial NOS-dependent mechanism [J]. J Ethnopharmacol , 2011 , 135 ( 2 ): 287 - 298 .
牛恒立 , 伏计能 , 马云海 . 红花提取物对大鼠心脏缺血再灌注的保护作用及机制研究 [J]. 中国现代应用药学 , 2019 , 36 ( 12 ): 1492 - 1497 .
ZENG C , JIANG W , YANG X Y , et al . Pretreatment with total flavonoid extract from dracocephalum moldavica l.attenuates ischemia reperfusion-induced apoptosis [J]. Sci Rep , 2018 , 8 ( 1 ): 17491 .
QING R , LIN J , LI C , et al . Study of the protective mechanisms of Compound Danshen Tablet (Fufang Danshen Pian)against myocardial ischemia/reperfusion injury via the Akt-eNOS signaling pathway in rats [J]. J Ethnopharmacol , 2014 , 156 : 190 - 198 .
李菊香 , 万磊 , 夏子荣 , 等 . 通心络胶囊对大鼠急性缺血再灌注损伤心肌的保护作用及信号转导 [J]. 中成药 , 2010 , 32 ( 4 ): 562 - 565 .
石月萍 , 杨关林 . 栝楼薤白半夏汤预处理保护缺血再灌注大鼠心肌PI3K/Akt通路机制 [J]. 中国中医基础医学杂志 , 2016 , 22 ( 7 ): 906 - 908 .
肖燕 , 丁亮 , 顾一煌 . 针灸对心肌缺血再灌注损伤细胞凋亡信号转导通路影响的研究进展 [J]. 针刺研究 , 2017 , 42 ( 5 ): 463 - 466 .
JI C C , SONG F , HUANG G Y , et al . The protective effects of acupoint gel embedding on rats with myocardial ischemia-reperfusion injury [J]. Life Sci , 2018 , 211 : 51 - 62 .
望庐山 , 梁凤霞 , 李佳 , 等 . 标本配穴电针干预对慢性心肌缺血模型大鼠凋亡相关蛋白表达与线粒体超微结构的影响 [J]. 中华中医药杂志 , 2019 , 34 ( 3 ): 1160 - 1165 .
ZHANG H R , BAI H , YANG E , et al . Effect of moxibustion preconditioning on autophagy-related proteins in rats with myocardial ischemia reperfusion injury [J], Ann Transl Med , 2019 , 7 ( 20 ): 559 .
0
Views
17
下载量
4
CSCD
Publicity Resources
Related Articles
Related Author
Related Institution
京公网安备11010802024621