线粒体障碍在糖尿病性心肌病中的作用及中医药研究进展Effect of mitochondrial dysfunction in diabetic cardiomyopathy and intervention of traditional Chinese medicine
田静;吕嵘;郭炜;
TIAN Jing;LV Rong;GUO Wei;Department of Pathology,Shanghai University of Traditional Chinese Medicine;
摘要(Abstract):
随着生活水平的提高和生活方式的改变,糖尿病的发病率及死亡率逐年上升。糖尿病发病10年后,约30%40%的患者至少会发生一种并发症,如糖尿病视网膜病变、肾脏病变或心血管病变等,这些慢性并发症大大影响患者生活质量和寿命。糖尿病性心肌病(diabetic cardiomyopathy,DCM)是指糖尿病患者出现左心室肥厚和舒张功能障碍,进而发展为收缩功能不全,且这种改变不与患者其他潜在的心血管疾病相关。线粒体是细胞内重要的能量代谢场所,它直接参与细胞生长、增殖、胞内信号转导和细胞凋亡等过程。近年来研究发现,线粒体障碍与DCM多个发病环节密切相关,其作用涉及糖脂代谢紊乱、氧化应激损伤、钙调控障碍、线粒体脱偶联、质量控制失衡以及MicroRNAs对线粒体的调节等多个方面。现代生物学研究进展同样启发中医药工作者以线粒体为靶向探寻有效治疗措施,越来越多的单味中药或其提取物(如人参、黄芪、葛根、黄连、姜黄、白藜芦醇等)以及复方制剂(如止消通脉宁、糖心乐、通心络等)被证实可以通过调节线粒体功能,改善糖尿病性心肌损伤。基于以上背景,该文将就线粒体障碍在DCM发病中的作用以及中医药在该领域的干预研究进展进行综述,以期为DCM的预防和治疗提供新的思路。
Diabetic cardiomyopathy(DCM) is characterized by left ventricular hypertrophy,myocardial fibrosis and diastolic dysfunction,which are uncorrelated with underlying coronary artery disease or hypertension.As an important metabolic organelle,mitochondria directly involve the process of cell growth,proliferation,signal transduction,apoptosis and so on.Recent studies have demonstrated a close correlation between the mitochondrial dysfunction and the pathogenesis of diabetic cardiomyopathy.The underlying effects of mitochondrial dysfunction in the progress of diabetic cardiomyopathy involve disturbed metabolism,oxidative stress,defective calcium handling,mitochondrial uncoupling,apoptosis,imbalance of mitochondrial quality control and regulation of MicroRNAs.Traditional Chinese medicines have been widely applied in clinic.Nowadays,more and more herbs of extracts of traditional Chinese medicines have been proved to ameliorate diabetic myocardial injury.Because the improvement of mitochondrial dysfunction has emerged as a promising therapeutic strategy,this review summarizes these effects of mitochondrial dysfunction in diabetic cardiomyopathy,and discusses the intervention studies of traditional Chinese medicine in the field,in expectation to provide new ideas for DCM prevention and treatment.
关键词(KeyWords):
糖尿病性心肌病;线粒体;中医药
diabetic cardiomyopathy;mitochondrial;traditional Chinese medicine
基金项目(Foundation): 国家自然科学基金项目(81473476,81373858);; 上海中医药大学研究生“创新能力培养”专项科研项目(B201703)
作者(Authors):
田静;吕嵘;郭炜;
TIAN Jing;LV Rong;GUO Wei;Department of Pathology,Shanghai University of Traditional Chinese Medicine;
DOI: 10.19540/j.cnki.cjcmm.20171027.014
参考文献(References):
- [1]Raza H,John A,Howarth F C.Alterations in glutathione redox metabolism,oxidative stress,and mitochondrial function in the left ventricle of elderly zucker diabetic Fatty rat heart[J].J Mol Sci,2012,13(12):16241.
- [2]Pham T,Loiselle D,Power A,et al.Mitochondrial inefficiencies and anoxic ATP hydrolysis capacities in diabetic rat heart[J].Am J Physiol Cell Physiol,2014,307(6):499.
- [3]Sloan C,Tuinei J,Nemetz K,et al.Central leptin signaling is required to normalize myocardial fatty acid oxidation rates in caloric restricted ob/ob mice[J].Diabetes,2011,60(5):1424.
- [4]Anderson E J,Kypson A P,Rodriguez E,et al.Substrate-specific derangements in mitochondrial metabolism and redox balance in the atrium of the type 2 diabetic human heart[J].J Am Coll Cardiol,2009,54(20):1891.
- [5]Chong C R,Clarke K,Levelt E.Metabolic remodelling in diabetic cardiomyopathy[J].Cardiovasc Res,2017,113:422.
- [6]Finck B N,Lehman J J,Leone T C,et al.The cardiac phenotype induced by PPARa overexpression mimics that caused by diabetes mellitus[J].J Clin Invest,2002,109(1):121.
- [7]Buchanan J,Mazumder P K,Hu P,et al.Reduced cardiac efficiency and altered substrate metabolism precedes the onset of hyperglycemia and contractile dysfunction in two mouse models of insulin resistance and obesity[J].Endocrinology,2005,146(12):5341.
- [8]Duncan J G,Finck B N.The PPARalpha-PGC-1alpha axis controls cardiac energy metabolism in healthy and diseased myocardium[J].PPAR Res,2008,doi:10.1155/2008/253817.
- [9]Boudina S,Sena S,O'Neill B T,et al.Reduced mitochondrial oxidative capacity and increased mitochondrial uncoupling impair myocardial energetics in obesity[J].Circulation,2005,112(17):2686.
- [10]Cai L,Wang Y,Zhou G,et al.Attenuation by metallothionein of early cardiac cell death via suppression of mitochondrial oxidative stress results in a prevention of diabetic cardiomyopathy[J].JAm Coll Cardiol,2006,48(8):1688.
- [11]Cong W,Ruan D,Xuan Y,et al.Cardiac-specific overexpression of catalase prevents diabetes-induced pathological changes by inhibiting NF-κB signaling activation in the heart[J].J Mol Cell Cardiol,2015,89:314.
- [12]Ivanovic'-Matic'S,Bogojevic'D,Martinovic'V,et al.Catalase inhibition in diabetic rats potentiates DNA damage and apoptotic cell death setting the stage for cardiomyopathy[J].J Physiol Biochem,2014,70(4):947.
- [13]Yakes F M,Van Houten B.Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress[J].Proc Natl Acad Sci U S A,1997,94(2):514.
- [14]Fauconnier J,Lanner J T,Zhang S J,et al.Insulin and inositol1,4,5-trisphosphate trigger abnormal cytosolic Ca2+transients and reveal mitochondrial Ca2+handling defects in cardiomyocytes of ob/ob mice[J].Diabetes,2005,54(8):2375.
- [15]Belke D D,Swanson E A,Dillmann W H.Decreased sarcoplasmic reticulum activity and contractility in diabetic db/db mouse heart[J].Diabetes,2004,53(12):3201.
- [16]Diaz-Juarez J,Suarez J,Cividini F,et al.Expression of the mitochondrial calcium uniporter in cardiac myocytes improves impaired mitochondrial calcium handling and metabolism in simulated hyperglycemia[J].Am J Physiol Cell Physiol,2016,311(6):C1005.
- [17]Rizzuto R,De Stefani D,Raffaello A,et al.Mitochondria as sensors and regulators of calcium signalling[J].Nat Rev Mol Cell Biol,2012,13(9):566.
- [18]O-Uchi J,Ryu S Y,Jhun B S,et al.Mitochondrial ion channels/transporters as sensors and regulators of cellular redox signaling[J].Antioxid Redox Signal,2014,21(6):987.
- [19]Boudina S,Sena S,Theobald H,et al.Mitochondrial energetics in the heart in obesity-related diabetes:direct evidence for increased uncoupled respiration and activation of uncoupling proteins[J].Diabetes,2007,56(10):2457.
- [20]Banke N H,Lewandowski E D.Impaired cytosolic NADH shuttling and elevated UCP3 contribute to inefficient citric acid cycle flux support of postischemic cardiac work in diabetic hearts[J].J Mol Cell Cardiol,2015,79(2):13.
- [21]Cole M A,Murray A J,Cochlin L E,et al.A high fat diet increases mitochondrial fatty acid oxidation and uncoupling to decrease efficiency in rat heart[J].Basic Res Cardiol,2011,106(3):447.
- [22]Bugger H,Boudina S,Hu X X,et al.Type 1 diabetic akita mouse hearts are insulin sensitive but manifest structurally abnormal mitochondria that remain coupled despite increased uncoupling protein 3[J].Diabetes,2008,57(11):2924.
- [23]Anderson E J,Rodriguez E,Anderson C A,et al.Increased propensity for cell death in diabetic human heart is mediated by mitochondrial-dependent pathways[J].Am J Physiol Heart Circ Physiol,2011,300(1):H118.
- [24]Amin A H,El-Missiry M A,Othman A I.Melatonin ameliorates metabolic risk factors,modulates apoptotic proteins,and protects the rat heart against diabetes-induced apoptosis[J].Eur J Pharmacol,2015,747(1):166.
- [25]Sun S,Yang S,Dai M,et al.The effect of Astragalus polysaccharides on attenuation of diabetic cardiomyopathy through inhibiting the extrinsic and intrinsic apoptotic pathways in high glucose stimulated H9C2 cells[J].BMC Complement Altern Med,2017,17(1):310.
- [26]Galloway C A,Yoon Y.Mitochondrial dynamics in diabetic cardiomyopathy[J].Antioxid Redox Signal,2015,22(17):1545.
- [27]Montaigne D,Marechal X,Coisne A,et al.Myocardial contractile dysfunction is associated with impaired mitochondrial function and dynamics in type 2 diabetic but not in obese patients[J].Circulation,2014,130(7):554.
- [28]Watanabe T,Saotome M,Nobuhara M,et al.Roles of mitochondrial fragmentation and reactive oxygen species in mitochondrial dysfunction and myocardial insulin resistance[J].Exp Cell Res,2014,323(2):314.
- [29]Yu W,Gao B,Li N,et al.Sirt3 deficiency exacerbates diabetic cardiac dysfunction:role of Foxo3A-Parkin-mediated mitophagy[J].Biochim Biophys Acta,2017,1863(8):1973.
- [30]Koncsos G,Varga Z V,Baranyai T,et al.Diastolic dysfunction in prediabetic male rats:role of mitochondrial oxidative stress[J].Am J Physiol Heart Circ Physiol,2016,311(4):H927.
- [31]Chang L T,Sun C K,Wang C Y,et al.Down regulation of peroxisome proliferator activated receptor gamma co-activator 1alpha in diabetic rats[J].Int Heart J,2006,47(6):901.
- [32]Dong F,Li Q,Sreejayan N,et al.Metallothionein prevents highfat diet induced cardiac contractile dysfunction:role of peroxisome proliferator activated receptor gamma coactivator 1alpha and mitochondrial biogenesis[J].Diabetes,2007,56(9):2201.
- [33]Finck B N.The PPAR regulatory system in cardiac physiology and disease[J].Cardiovasc Res,2007,73(2):269.
- [34]Mitra R,Nogee D P,Zechner J F,et al.The transcriptional coactivators,PGC-1αandβ,cooperate to maintain cardiac mitochondrial function during the early stages of insulin resistance[J].J Mol Cell Cardiol,2012,52(3):701.
- [35]Baseler W A,Thapa D,Jagannathan R,et al.miR-141 as a regulator of the mitochondrial phosphate carrier(Slc25a3)in the type1 diabetic heart[J].Am J Physiol Cell Physiol,2012,303(12):1244.
- [36]Jagannathan R,Thapa D,Nichols C E,et al.Translational regulation of the mitochondrial genome following redistribution of mitochondrial microRNA in the diabetic heart[J].Circ Cardiovasc Genet,2015,8(6):785.
- [37]Yu H T,Zhen J,Pang B,et al.Ginsenoside Rg1ameliorates oxidative stress and myocardial apoptosis in streptozotocin-induced diabetic rats[J].J Zhejiang Univ Sci B,2015,16(5):344.
- [38]Wu Y,Xia Z Y,Dou J,et al.Protective effect of ginsenoside Rb1against myocardial ischemia/reperfusion injury in streptozotocininduced diabetic rats[J].Mol Biol Rep,2011,38(7):4327.
- [39]Sun M,Huang C,Wang C,et al.Ginsenoside Rg3improves cardiac mitochondrial population quality:mimetic exercise training[J].Biochem Biophys Res Commun,2013,441(1):169.
- [40]曹琼丹,杨育红,于胜男,等.黄芪甲苷对Ⅰ型糖尿病大鼠心肌细胞PGC-1α和NRF-1表达的影响[J].中国药理学通报,2015,31(8):1096.
- [41]王凤杰,邓江,苏慧,等.黄芪多糖对2型糖尿病大鼠心肌UCP2表达和AMPK活性的影响[J].武汉大学学报,2009,30(5):574.
- [42]Chen W,Xia Y,Zhao X,et al.The critical role of Astragalus polysaccharides for the improvement of PPRAa-mediated lipotoxicity in diabetic cardiomyopathy[J].PLo S ONE,2012,7(10):e45541.
- [43]Sun S,Yang S,Dai M,et al.The effect of Astragalus polysaccharides on attenuation of diabetic cardiomyopathy through inhibiting the extrinsic and intrinsic apoptotic pathways in high glucose stimulated H9C2 cells[J].BMC Complement Altern Med,2017,17(1):310.
- [44]顾掌生,王大力.葛根素抗糖尿病大鼠心肌线粒体氧化应激损伤作用研究[J].中华中医药学刊,2010,28(10):2197.
- [45]Yu W,Zha W,Guo S.Flos Puerariae extract prevents myocardial apoptosis via attenuation oxidative stress in streptozotocin-induced diabetic mice[J].PLo S ONE,2014,9(5):e98044.
- [46]张玲,庞莉,高俊虹,等.葛根素对糖尿病大鼠心肌细胞凋亡及相关蛋白表达的影响[J].中国中医基础医学杂志,2011,17(3):323.
- [47]Chang W,Chen L,Hatch G M.Berberine treatment attenuates the palmitate-mediated inhibition of glucose uptake and consumption through increased 1,2,3-triacyl-sn-glycerol synthesis and accumulation in H9c2 cardiomyocytes[J].Biochim Biophys Acta,2016,1861(4):352.
- [48]Chen K,Li G,Geng F,et al.Berberine reduces ischemia/reperfusion-induced myocardial apoptosis via activating AMPK and PI3K-Akt signaling in diabetic rats[J].Apoptosis,2014,19(6):946.
- [49]Trujillo J,Granados-Castro L F,Zazueta C,et al.Mitochondria as a target in the therapeutic properties of curcumin[J].Arch Pharm(Weinheim),2014,347(12):873.
- [50]Jiang S,Han J,Li T,et al.Curcumin as potential protective compound against cardiac diseases[J].Pharmacol Res,2017,119(5):373.
- [51]Zeng C,Zhong P,Zhao Y,et al.Curcumin protects hearts from FFA-induced injury by activating Nrf2 and inactivating NF-κBboth in vitro and in vivo[J].J Mol Cell Cardiol,2015,79(2):1.
- [52]Aziz M T,El Ibrashy I N,Mikhailidis D P,et al.Signaling mechanisms of a water soluble curcumin derivative in experimental type1 diabetes with cardiomyopathy[J].Diabetol Metab Syndr,2013,5(1):13.
- [53]Na L X,Zhang Y L,Li Y,et al.Curcumin improves insulin resistance in skeletal muscle of rats[J].Nutr Metab Cardiovasc Dis,2011,21(7),526.
- [54]Na L X,Li Y,Pan H Z,et al.Curcuminoids exert glucose-lowering effect in type 2 diabetes by decreasing serum free fatty acids:a double-blind,placebo-controlled trial[J].Mol Nutr Food Res,2013,57(9):1569.
- [55]Abo-Salem O M,Harisa G I,Ali T M,et al.Curcumin ameliorates streptozotocin-induced heart injury in rats[J].J Biochem Mol Toxicol,2014,28(6):263.
- [56]Soto-Urquieta M G,Sergio López-Briones,Victoriano PérezVázquez1,et al.Curcumin restores mitochondrial functions and decreases lipid peroxidation in liver and kidneys of diabetic db/db mice[J].Biol Res,2014,47(1):74.
- [57]Bai Y,Cui W,Xin Y,et al.Prevention by sulforaphane of diabetic cardiomyopathy is associated with up-regulation of Nrf2 expression and transcription activation[J].J Mol Cell Cardiol,2013,57:82.
- [58]Zhang Z,Wang S,Zhou S,et al.Sulforaphane prevents the development of cardiomyopathy in type 2 diabetic mice probably by reversing oxidative stress-induced inhibition of LKB1/AMPK pathway[J].J Mol Cell Cardiol,2014,77:42.
- [59]Beaudoin M S,Perry C G,Arkell A M,et al.Impairments in mitochondrial palmitoyl-Co A respiratory kinetics that precede development of diabetic cardiomyopathy are prevented by resveratrol in ZDF rats[J].J Physiol,2014,592(12):2519.
- [60]Mohammadshahi M,Haidari F,Soufi F G.Chronic resveratrol administration improves diabetic cardiomyopathy in part by reducing oxidative stress[J].Cardiol J,2014,21(1):39.
- [61]Guo S,Yao Q,Ke Z,et al.Resveratrol attenuates high glucose-induced oxidative stress and cardiomyocyte apoptosis through AMPK[J].Mol Cell Endocrinol,2015,412:85.
- [62]Ma S,Feng J,Zhang R,et al.SIRT1 activation by resveratrol alleviates cardiac dysfunction via mitochondrial regulation in diabetic cardiomyopathy mice[J].Oxid Med Cell Longev,2017,doi:10.1155/2017/4602715.
- [63]Fang W J,Wang C J,He Y,et al.Resveratrol alleviates diabetic cardiomyopathy in rats by improving mitochondrial function through PGC-1αdeacetylation[J].Acta Pharmacol Sin,2017,doi:10.1038/aps.2017.50.
- [64]杨晓辉,赵凤志,戴欣,等.止消通脉宁对糖尿病心肌超微结构和酶组化的影响[J].北京中医药大学学报,1998,21(2):32.
- [65]赵莉平,安荣,丁雯,等.糖心乐对糖尿病心肌病大鼠心功能及心肌细胞凋亡的影响[J].陕西中医学院学报,2014,35(5):615.
- [66]刘馨,徐军,张晓妍.通心络对糖尿病心肌病大鼠左室功能及心肌细胞凋亡的影响[J].山东医药,2011,51(5):33.