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研究生:朱俊憲
研究生(外文):Chun-Hsien
論文名稱:類胰島素生長因子-II接受體過度表現誘發心肌肥大、凋亡與纖維化之分子機轉探討:1.下游G蛋白訊息路徑之轉換活化;2.類胰島素生長因子-II接受體基因之調控機轉;3.全新類胰島素生長因子-II接受體之異構體發現
論文名稱(外文):Molecular mechanisms of the overactivated IGF2R signaling pathway inducing cardiac hypertrophy, apoptosis and fibrosis:1. Role of the downstream G protein signaling switch;2. Transcriptional regulation of the IGF2R gene;3. Functional revealed of the novel
指導教授:陳凌雲陳凌雲引用關係
學位類別:博士
校院名稱:中山醫學大學
系所名稱:生化暨生物科技研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2008
畢業學年度:96
語文別:中文
論文頁數:175
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心肌肥大為心臟在面對各種刺激下的適應性反應,但隨著壓力不斷地增加且無法解除將造成心肌細胞凋亡導致心衰竭的發生。先前的研究發現在心臟病變的過程類胰島素生長因子-II(IGF-II)以及類胰島素生長因子第二型接受體(IGF2R)基因會大量上升可能是導致心肌肥大和凋亡以及心臟的纖維化的主因。但是心臟中詳細之IGF2R訊息路徑和其基因如何被調節以及其在心臟病變分子機轉中所扮演的角色仍不清楚;另外,我們將介紹一個全新的IGF2R基因異構體:2R-α的發現過程。首先,我們發現到在人類心肌梗塞和心結痂的檢體中較正常心組織有較高的IGF2R蛋白表現。為了專一性的活化IGF2R訊息路徑,我們採用兩種實驗策略:1.拮抗劑AG1024和IGF1R siRNA阻斷IGF1R訊息路徑;2.使用具專一性的Leu27IGF-II結合於IGF2R以避免IGF1R和InR的干擾。由實驗結果得知,IGF2R為一G protein-coupled receptor,在經IGF-II活化後改變其與small G-protein之結合能力。活化的IGF2R訊息路徑會經由Gαq、PKC-α/ CaMKII和calcineurin分別造成病理性心肌肥大和粒腺體依賴型的細胞凋亡,其完全不同於IGF1R訊息路徑所誘發的生理性心肌肥大和心肌的存活作用。我們同時發現IGF2R訊息路徑會透過活化MMP-9和Plasminogen Activators (PAs)影響著extra cellular matrix (ECM)的不正常的重組作用而導致心肌纖維化的發生。接著,我們進一步探討心臟病變過程中,調控igf2r基因大量表達的分子機轉。首先我們從兩個實驗方向進行探討:1.Epigenomic modification: 含DNA甲基化(DNA methylation)和組蛋白的乙醯化(Histone acetylation);2.尋找可能參與啟動子活性(Promoter activity)的轉錄活化因子。實驗發現,於病態刺激下所造成之igf2r基因表現主要經由影響Histone acetylation造成,而與DNA methylation無關。利用建構含不同片段之igf2r promoter的報導基因載體,我們血管昇壓素(ANGII)會促使抑制性轉錄因子:熱刺激因子(HSF-1)從igf2r基因promoter上的HSF-Binding Element (HBE; -725~-704 bp)移除,進而開啟igf2r基因的表現。我們亦經由Rapid amplification of cDNA ends (RACE) PCR定義出一個具有4656bp長度的mRNA,起始於IGF2R基因intron 9的第645 bp,包含著exon 10-35 的序列,終止於intron 36的第455 bp位置。其可轉譯成具有1358個氨基酸的蛋白質,我們命名此IGF2R的異構體蛋白質為2R-α,並進一步探討其生理功能。綜合上述,我們認為透過抑制IGF2R訊息路徑和其基因之表達將提供治療心肌肥大和凋亡以及心臟纖維化進而減緩心衰竭進程的機會。同時相信,2R-α的發現與進一步功能的探討將對由IGF系統異常所造成的疾病帶來新的思考空間以及新的解決模式。

Cardiac hypertrophy is an adaptive response of heart under varied stresses. When stress has been accumulated, the transition from physiological hypertrophy to pathological hypertrophy results in promotion of heart failure. Our previous studies demonstrated upregulations of insulin-like growth factor II (IGF-II) and mannose 6-phosphate/IGF-II receptor (IGF2R) dose-dependently correlating with the progression of heart disease following complete abdominal aorta ligation, may play a critical role in angiotensin II (ANGII)-induced cardiomyocyte apoptosis. However, the detailed mechanisms of IGF2R in the promotion of heart failure in response to IGF-II remain unclear. Additionally, how igf2r gene up-regulation in response to pathological stresses is also poorly understood. Therefore, in the study I, we found a significant association of IGF2R overexpression with myocardial infarction and myocardial scars. Results of specifically activating IGF2R signaling through either inhibition of the IGF1R activity by IGF1R siRNA and AG1024 or using Leu27IGF-II analog, a ligand interact only with the IGF2R, revealed that IGF2R activated by IGF-II binding acted like a G protein-coupled receptor to activate PKC-α/CaMKII and calcineurin by association with Gαq, leading to pathological hypertrophy and mitochondria-dependent cell apoptosis in cardiomyocytes. Furthermore, we also found that IGF2R signaling activation disrupted the balance of MMP-9/TIMP-2 expressions and increased plasminogen activator (PAs) expression, resulting in the development of myocardial remodeling. In study II, we found the histone acetylation, but not the DNA methylation, is required for the induction of igf2r gene by ANGII. Moreover, when responding to ANGII, HSF-1, identified as a suppressor of igf2r gene under normal condition, slipped out of the HSF-binding element within the IGF2R promoter that contributes up-regulation of igf2r gene expression. Taken together, our study provides new insight into the gene regulation of IGF2R and the role of the IGF2R in the pathogenesis of cardiac disease. Suppression of IGF2R gene expression and its signaling pathways may be a good strategy to prevent the progression of heart failure. We also discovered a novel gene of IGF2R isoform, 2R-α, which transcripts 4656 nucleic acid mRNA examined by using the rapid amplification of cDNA ends (RACE) PCR and northern blots. After compared with IGF2R mRNA sequences, regardless of the same sequences from IGF2R’s exon 10 to exon 35, the 2R-α gene sequence unexpectedly comprise a partial fragment of intron 9 (645~806 bp) of IGF2R in its 5’ region and a partial fragment of intron 35 (1~455 bp) in its 3’ region. In addition, we found a new TATA box exists in the 5’ upstream region of 2R-α gene and its coding region starts at the 14 bp of exon 10, then stops in the 48bp of intron 35 that may encode a 1358 amino acids protein predicted by Open Reading Frame Finder. Furthermore, creating the antibody that recognized the 15 amino acidic sequence in N terminal:AYDESEDDTSDTTPC of predicted 2R-α protein sequences to confirm the translation of gene transcript into the 2R-α protein. Further to identify the role and function of this novel 2R-α gene in the future may provide a new concept of IGFs in regulating cell physiology and heart function.

壹、中文摘要......................................4
貳、英文摘要......................................6
參、縮寫表........................................8
肆、前言..........................................10
1. 心衰竭之進程:心肌肥大、凋亡與纖維.............10
2. 類胰島素生長因子...............................14
3. 類胰島素生長因子與心臟疾病之關係...............17
伍、實驗動機......................................19
陸、實驗方法與材料................................20
1. 實驗材料.......................................20
1.1 實驗動物......................................20
1.2 實驗化學試劑..................................20
1.3 實驗儀器......................................23
1.4 實驗使用之抗體................................24
1.5 實驗使用之DNA引子.............................28
1.6 實驗使用之抑制劑..............................33
1.7 實驗使用之KIT.................................35
1.8 實驗使用之載體................................37
1.9 實驗使用之組織晶片............................37
2. 實驗方法.......................................37
2.1 心肌細胞培養..................................37
2.2 細胞大小分析(Measurement of Cell Surface Area)38
2.3 組織免疫染色(Immunohistochemical Analysis)....38
2.4 蛋白質翠取與西方氏點墨法(Protein Extraction
and Western Blot Analysis)........................38
2.5免疫沉澱分析(Immunoprecipitation assay)........40
2.6 TUNEL staining................................40
2.7粒腺體膜電位偵測
(Mitochondrial Membrane Potential)................41
2.8 鈣離子染色
(Measurement of Intracellular Calcium)............41
2.9 shRNA之建構與轉殖
(shRNA/ siRNA and Transfection)...................41
2.10 Gelatin Zymography...........................41
2.11 RNA萃取與RT-PCR
(Total RNA Extraction and RT-PCR).................41
2.12 Bisulfite Modification (Conversion) of DNA and Methylation specific PCR (MSP)....................44
2.13 Chromatin Immunopreciptation (ChIP)..........45
2.14 Electrophoretic Mobility Shift Assay
(EMSA assay)......................................46
2.15 IGF2R promoter Luciferase Reporter c
onstruction and Assay of Luciferase activity......47
2.16 Rapid amplification of cDNA ends (RACE) PCR..47
2.17 探針製備與北方氏點墨法
(Random primed DNA labeling and Northern Blot)....48
2.18 統計.........................................48
柒、實驗結果......................................49
1. IGF2R所誘發之訊息路徑對心肌細胞之影響..........49
1.1 IGF2R所誘發之訊息路徑與心肌肥大之關係.........49
1.2 IGF2R所誘發之訊息路徑與心肌凋亡之關係.........51
1.3 IGF2R所誘發之訊息路徑與心肌重組之關係.........58
2. IGF2R基因調控之分子機轉........................61
2.1 IGF2R基因在Epigenomic Modification上的調控....61
2.2 IGF2R基因在起動子活性(Promoter Activity)
上的調控..........................................64
3. 定義一個全新的IGF2R異構體(isoform)蛋白:2R-.....67
捌、討論..........................................70
1. IGF-I和IGF-II功能同異之處......................70
2. 探討IGF-II之生理功能時,必須考慮IGF2R所誘發
之訊息路徑........................................71
3. 探討IGF2R訊息路徑的困難與策略..................71
4. IGF1R的活性決定IGF-II的作用能力................72
5. IGF2R與G-protein...............................73
6. IGF2R與IGF1R訊息路徑在心臟病變之比較...........73
7.使用IGF system在心臟疾病之治療策略..............76
8.不同的心臟病變的刺激下對於igf-2r基因表現之影響..77
9. igf-2r基因之調控與DNA的甲基化..................77
10. igf-2r基因之調控與Histone的乙醯化.............78
11. igf-2r基因之調控與heat shock factor (HSF).....79
12. 2R-
玖、參考文獻......................................82
拾、圖表..........................................96
附錄..............................................170


1.Lips DJ, deWindt LJ, van Kraaij DJ, Doevendans PA 2003 Molecular determinants of myocardial hypertrophy and failure: alternative pathways for beneficial and maladaptive hypertrophy. Eur Heart J 24:883-96
2.Olivetti G, Abbi R, Quaini F, Kajstura J, Cheng W, Nitahara JA, Quaini E, Di Loreto C, Beltrami CA, Krajewski S, Reed JC, Anversa P 1997 Apoptosis in the failing human heart. N Engl J Med 336:1131-41
3.Heineke J, Molkentin JD 2006 Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev Mol Cell Biol 7:589-600
4.McMullen JR, Jennings GL 2007 Differences between pathological and physiological cardiac hypertrophy: novel therapeutic strategies to treat heart failure. Clin Exp Pharmacol Physiol 34:255-62
5.Olson EN 2004 A decade of discoveries in cardiac biology. Nat Med 10:467-74
6.Frey N, Olson EN 2003 Cardiac hypertrophy: the good, the bad, and the ugly. Annu Rev Physiol 65:45-79
7.van Empel VP, De Windt LJ 2004 Myocyte hypertrophy and apoptosis: a balancing act. Cardiovasc Res 63:487-99
8.Anselmi A, Gaudino M, Baldi A, Vetrovec GW, Bussani R, Possati G, Abbate A 2008 Role of apoptosis in pressure-overload cardiomyopathy. J Cardiovasc Med (Hagerstown) 9:227-32
9.Katz AM 1995 Cell death in the failing heart: role of an unnatural growth response to overload. Clin Cardiol 18:IV36-44
10.Kuethe F, Sigusch HH, Bornstein SR, Hilbig K, Kamvissi V, Figulla HR 2007 Apoptosis in patients with dilated cardiomyopathy and diabetes: a feature of diabetic cardiomyopathy? Horm Metab Res 39:672-6
11.Burke AP, Virmani R 2007 Pathophysiology of acute myocardial infarction. Med Clin North Am 91:553-72; ix
12.Nishikawa T, Ishiyama S, Nagata M, Sakomura Y, Nakazawa M, Momma K, Hiroe M, Kasajima T 1999 Programmed cell death in the myocardium of arrhythmogenic right ventricular cardiomyopathy in children and adults. Cardiovasc Pathol 8:185-9
13.Buja LM. Myocardial ischemia and reperfusion injury. 2005 Cardiovasc Pathol. 14:170-5.
14.Tabas I 2007 Apoptosis and efferocytosis in mouse models of atherosclerosis. Curr Drug Targets 8:1288-96
15.Purevjav E, Nelson DP, Varela JJ, Jimenez S, Kearney DL, Sanchez XV, DeFreitas G, Carabello B, Taylor MD, Vatta M, Shearer WT, Towbin JA, Bowles NE 2007 Myocardial Fas ligand expression increases susceptibility to AZT-induced cardiomyopathy. Cardiovasc Toxicol 7:255-63
16.James TN, St Martin E, Willis PW, 3rd, Lohr TO 1996 Apoptosis as a possible cause of gradual development of complete heart block and fatal arrhythmias associated with absence of the AV node, sinus node, and internodal pathways. Circulation 93:1424-38
17.Haudek SB, Taffet GE, Schneider MD, Mann DL 2007 TNF provokes cardiomyocyte apoptosis and cardiac remodeling through activation of multiple cell death pathways. J Clin Invest 117:2692-701
18.Desagher S, Martinou JC 2000 Mitochondria as the central control point of apoptosis. Trends Cell Biol. 10:369-77
19.Vasan RS, Benjamin EJ 2001 Diastolic heart failure--no time to relax. N Engl J Med 344:56-9
20.Gaertner R, Jacob MP, Prunier F, Angles-Cano E, Mercadier JJ, Michel JB 2005 The plasminogen-MMP system is more activated in the scar than in viable myocardium 3 months post-MI in the rat. J Mol Cell Cardiol 38:193-204
21.Roldan V, Marin F, Gimeno JR, Ruiz-Espejo F, Gonzalez J, Feliu E, Garcia-Honrubia A, Saura D, de la Morena G, Valdes M, Vicente V 2008 Matrix metalloproteinases and tissue remodeling in hypertrophic cardiomyopathy. Am Heart J 156:85-91
22.Heymans S, Pauschinger M, De Palma A, Kallwellis-Opara A, Rutschow S, Swinnen M, Vanhoutte D, Gao F, Torpai R, Baker AH, Padalko E, Neyts J, Schultheiss HP, Van de Werf F, Carmeliet P, Pinto YM 2006 Inhibition of urokinase-type plasminogen activator or matrix metalloproteinases prevents cardiac injury and dysfunction during viral myocarditis. Circulation 114:565-73
23.Ahmed SH, Clark LL, Pennington WR, Webb CS, Bonnema DD, Leonardi AH, McClure CD, Spinale FG, Zile MR 2006 Matrix metalloproteinases/tissue inhibitors of metalloproteinases: relationship between changes in proteolytic determinants of matrix composition and structural, functional, and clinical manifestations of hypertensive heart disease. Circulation 113:2089-96
24.Heymans S, Lupu F, Terclavers S, Vanwetswinkel B, Herbert JM, Baker A, Collen D, Carmeliet P, Moons L 2005 Loss or inhibition of uPA or MMP-9 attenuates LV remodeling and dysfunction after acute pressure overload in mice. Am J Pathol 166:15-25
25.Heymans S, Luttun A, Nuyens D, Theilmeier G, Creemers E, Moons L, Dyspersin GD, Cleutjens JP, Shipley M, Angellilo A, Levi M, Nube O, Baker A, Keshet E, Lupu F, Herbert JM, Smits JF, Shapiro SD, Baes M, Borgers M, Collen D, Daemen MJ, Carmeliet P 1999 Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure. Nat Med 5:1135-42
26.Peterson JT, Li H, Dillon L, Bryant JW 2000 Evolution of matrix metalloprotease and tissue inhibitor expression during heart failure progression in the infarcted rat. Cardiovasc Res 46:307-15
27.Creemers EE, Cleutjens JP, Smits JF, Daemen MJ 2001 Matrix metalloproteinase inhibition after myocardial infarction: a new approach to prevent heart failure? Circ Res 89:201-10
28.Jones JI, Clemmons DR 1995 Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 16:3-34
29.Baker J, Liu JP, Robertson EJ, Efstratiadis A 1993 Role of insulin-like growth factors in embryonic and postnatal growth. Cell 75:73-82
30.Constancia M, Hemberger M, Hughes J, Dean W, Ferguson-Smith A, Fundele R, Stewart F, Kelsey G, Fowden A, Sibley C, Reik W 2002 Placental-specific IGF-II is a major modulator of placental and fetal growth. Nature 417:945-8
31.Abuzzahab MJ, Schneider A, Goddard A, Grigorescu F, Lautier C, Keller E, Kiess W, Klammt J, Kratzsch J, Osgood D, Pfaffle R, Raile K, Seidel B, Smith RJ, Chernausek SD 2003 IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med 349:2211-22
32.Lau MM, Stewart CE, Liu Z, Bhatt H, Rotwein P, Stewart CL 1994 Loss of the imprinted IGF2/cation-independent mannose 6-phosphate receptor results in fetal overgrowth and perinatal lethality. Genes Dev 8:2953-63
33.Saltiel AR, Kahn CR 2001 Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414:799-806
34.McMullen JR, Shioi T, Huang WY, Zhang L, Tarnavski O, Bisping E, Schinke M, Kong S, Sherwood MC, Brown J, Riggi L, Kang PM, Izumo S 2004 The insulin-like growth factor 1 receptor induces physiological heart growth via the phosphoinositide 3-kinase(p110alpha) pathway. J Biol Chem 279:4782-93
35.Boker C, von Figura K, Hille-Rehfeld A 1997 The carboxy-terminal peptides of 46 kDa and 300 kDa mannose 6-phosphate receptors share partial sequence homology and contain information for sorting in the early endosomal pathway. J Cell Sci 110 (Pt 8):1023-32
36.Braulke T 1999 Type-2 IGF receptor: a multi-ligand binding protein. Horm Metab Res 31:242-6
37.Hawkes C, Jhamandas JH, Harris KH, Fu W, MacDonald RG, Kar S 2006 Single transmembrane domain insulin-like growth factor-II/mannose-6-phosphate receptor regulates central cholinergic function by activating a G-protein-sensitive, protein kinase C-dependent pathway. J Neurosci 26:585-96
38.McKinnon T, Chakraborty C, Gleeson LM, Chidiac P, Lala PK 2001 Stimulation of human extravillous trophoblast migration by IGF-II is mediated by IGF type 2 receptor involving inhibitory G protein(s) and phosphorylation of MAPK. J Clin Endocrinol Metab 86:3665-74
39.Nishimoto I, Hata Y, Ogata E, Kojima I 1987 Insulin-like growth factor II stimulates calcium influx in competent BALB/c 3T3 cells primed with epidermal growth factor. Characteristics of calcium influx and involvement of GTP-binding protein. J Biol Chem 262:12120-6
40.Murayama Y, Okamoto T, Ogata E, Asano T, Iiri T, Katada T, Ui M, Grubb JH, Sly WS, Nishimoto I 1990 Distinctive regulation of the functional linkage between the human cation-independent mannose 6-phosphate receptor and GTP-binding proteins by insulin-like growth factor II and mannose 6-phosphate. J Biol Chem 265:17456-62
41.McDonald A, Williams RM, Regan FM, Semple RK, Dunger DB 2007 IGF-I treatment of insulin resistance. Eur J Endocrinol 157 Suppl 1:S51-6
42.Tao Y, Pinzi V, Bourhis J, Deutsch E 2007 Mechanisms of disease: signaling of the insulin-like growth factor 1 receptor pathway--therapeutic perspectives in cancer. Nat Clin Pract Oncol 4:591-602
43.LeRoith D, Yakar S 2007 Mechanisms of disease: metabolic effects of growth hormone and insulin-like growth factor 1. Nat Clin Pract Endocrinol Metab 3:302-10
44.Hartog H, Wesseling J, Boezen HM, van der Graaf WT 2007 The insulin-like growth factor 1 receptor in cancer: old focus, new future. Eur J Cancer 43:1895-904
45.Lee SD, Chu CH, Huang EJ, Lu MC, Liu JY, Liu CJ, Hsu HH, Lin JA, Kuo WW, Huang CY 2006 Roles of insulin-like growth factor II in cardiomyoblast apoptosis and in hypertensive rat heart with abdominal aorta ligation. Am J Physiol Endocrinol Metab 291:E306-14
46.Kluge A, Zimmermann R, Munkel B, Verdouw PD, Schaper J, Schaper W 1995 Insulin-like growth factor II is an experimental stress inducible gene in a porcine model of brief coronary occlusions. Cardiovasc Res 29:708-16
47.Miyashita T, Takeishi Y, Takahashi H, Kato S, Kubota I, Tomoike H 2001 Role of calcineurin in insulin-like growth factor-1-induced hypertrophy of cultured adult rat ventricular myocytes. Jpn Circ J 65:815-9
48.Adachi S, Ito H, Akimoto H, Tanaka M, Fujisaki H, Marumo F, Hiroe M 1994 Insulin-like growth factor-II induces hypertrophy with increased expression of muscle specific genes in cultured rat cardiomyocytes. J Mol Cell Cardiol 26:789-95
49.Kooijman R 2006 Regulation of apoptosis by insulin-like growth factor (IGF)-I. Cytokine Growth Factor Rev 17:305-23
50.O''Connor R, Fennelly C, Krause D 2000 Regulation of survival signals from the insulin-like growth factor-I receptor. Biochem Soc Trans 28:47-51
51.Colao A 2008 The GH/IGF axis and the cardiovascular system: clinical implications. Clin Endocrinol (Oxf)
52.Roberts CT, Owens JA, Sferruzzi-Perri AN 2008 Distinct actions of insulin-like growth factors (IGFs) on placental development and fetal growth: lessons from mice and guinea pigs. Placenta 29 Suppl A:S42-7
53.Huang CY, Hao LY, Buetow DE 2002 Insulin-like growth factor-II induces hypertrophy of adult cardiomyocytes via two alternative pathways. Cell Biol Int 26:737-9
54.Chen Z, Ge Y, Kang JX 2004 Down-regulation of the M6P/IGF-II receptor increases cell proliferation and reduces apoptosis in neonatal rat cardiac myocytes. BMC Cell Biol 5:15
55.Kuo WW, Liu CJ, Chen LM, Wu CH, Chu CH, Liu JY, Lu MC, Lin JA, Lee SD, Huang CY 2006 Cardiomyoblast apoptosis induced by insulin-like growth factor (IGF)-I resistance is IGF-II dependent and synergistically enhanced by angiotensin II. Apoptosis 11:1075-89
56.Najafi F, Dobson AJ, Hobbs M, Jamrozik K 2008 Late-onset heart failure after myocardial infarction: Trends in incidence and survival. Eur J Heart Fail
57.Song LN, Coghlan M, Gelmann EP 2004 Antiandrogen effects of mifepristone on coactivator and corepressor interactions with the androgen receptor. Mol Endocrinol 18:70-85
58.Ibarra C, Estrada M, Carrasco L, Chiong M, Liberona JL, Cardenas C, Diaz-Araya G, Jaimovich E, Lavandero S 2004 Insulin-like growth factor-1 induces an inositol 1,4,5-trisphosphate-dependent increase in nuclear and cytosolic calcium in cultured rat cardiac myocytes. J Biol Chem 279:7554-65
59.Li LC, Dahiya R 2002 MethPrimer: designing primers for methylation PCRs. Bioinformatics 18:1427-31
60.Beukers MW, Oh Y, Zhang H, Ling N, Rosenfeld RG 1991 [Leu27] insulin-like growth factor II is highly selective for the type-II IGF receptor in binding, cross-linking and thymidine incorporation experiments. Endocrinology 128:1201-3
61.Chu CH, Tzang BS, Chen LM, Kuo CH, Cheng YC, Chen LY, Tsai FJ, Tsai CH, Kuo WW, Huang CY 2008 IGF-II/mannose-6-phosphate receptor signaling induced cell hypertrophy and atrial natriuretic peptide/BNP expression via Galphaq interaction and protein kinase C-alpha/CaMKII activation in H9c2 cardiomyoblast cells. J Endocrinol 197:381-90
62.Motyka B, Korbutt G, Pinkoski MJ, Heibein JA, Caputo A, Hobman M, Barry M, Shostak I, Sawchuk T, Holmes CF, Gauldie J, Bleackley RC 2000 Mannose 6-phosphate/insulin-like growth factor II receptor is a death receptor for granzyme B during cytotoxic T cell-induced apoptosis. Cell 103:491-500
63.Deutsch E, Maggiorella L, Wen B, Bonnet ML, Khanfir K, Frascogna V, Turhan AG, Bourhis J 2004 Tyrosine kinase inhibitor AG1024 exerts antileukaemic effects on STI571-resistant Bcr-Abl expressing cells and decreases AKT phosphorylation. Br J Cancer 91:1735-41
64.Ikezu T, Okamoto T, Giambarella U, Yokota T, Nishimoto I 1995 In vivo coupling of insulin-like growth factor II/mannose 6-phosphate receptor to heteromeric G proteins. Distinct roles of cytoplasmic domains and signal sequestration by the receptor. J Biol Chem 270:29224-8
65.Rockman HA, Koch WJ, Lefkowitz RJ 2002 Seven-transmembrane-spanning receptors and heart function. Nature 415:206-12
66. Chu CH, Huang CY, Kuo WW, Lin JA, Tsai FJ, Tsai CH, Chu CY, Kuo WH, Chen LM, Chen LY 2008 IGF-II synergistically enhances AG1024-induced H9c2 cardiomyoblast cell apoptosis via the interaction of IGF2R with Gα proteins and its downstream PKA and PLC-β modulators. Chin J Physiol. Accepted
67.Bers DM, Guo T 2005 Calcium signaling in cardiac ventricular myocytes. Ann N Y Acad Sci 1047:86-98
68.Yue C, Sanborn BM 2001 KN-93 inhibition of G protein signaling is independent of the ability of Ca2+/calmodulin-dependent protein kinase II to phosphorylate phospholipase Cbeta3 on 537-Ser. Mol Cell Endocrinol 175:149-56
69. Chen RJ, Kuo WW, Lee SD, Hwang JM, Chu CY, Kuo WH, Tsai FJ, Tsai CH, Chen LM, Huang CY, Chu CH 2008 Leu27IGF-II plays opposite role with IGF-I to induce H9c2 cardiomyoblast cell apoptosis via Gaq signaling. Mol Cell Endocrinol. Revised
71.Riedl SJ, Shi Y 2004 Molecular mechanisms of caspase regulation during apoptosis. Nat Rev Mol Cell Biol 5:897-907
72.Harris MH, Thompson CB 2000 The role of the Bcl-2 family in the regulation of outer mitochondrial membrane permeability. Cell Death Differ 7:1182-91
73.Breckenridge DG, Xue D 2004 Regulation of mitochondrial membrane permeabilization by BCL-2 family proteins and caspases. Curr Opin Cell Biol 16:647-52
74.Lim HW, Molkentin JD 1999 Calcineurin and human heart failure. Nat Med 5:246-7
75.Fan G, Jiang YP, Lu Z, Martin DW, Kelly DJ, Zuckerman JM, Ballou LM, Cohen IS, Lin RZ 2005 A transgenic mouse model of heart failure using inducible Galpha q. J Biol Chem 280:40337-46
76. Chu CH, Tzang BS, Chen LM, Liu CJ, Tsai FJ, Tsai CH, Lin JA, Bau DT, Kuo WW, Huang CY 2008 Specific Activated IGF2R Induces Mitochondria-dependent Apoptosis through Gaq and Downstream Calcineurin Signaling in Myocardial Cells. Endocrinology Revised
77.Godar S, Horejsi V, Weidle UH, Binder BR, Hansmann C, Stockinger H 1999 M6P/IGFII-receptor complexes urokinase receptor and plasminogen for activation of transforming growth factor-beta1. Eur J Immunol 29:1004-13
78.Ghosh P, Dahms NM, Kornfeld S 2003 Mannose 6-phosphate receptors: new twists in the tale. Nat Rev Mol Cell Biol 4:202-12
79.Leask A, Abraham DJ 2004 TGF-beta signaling and the fibrotic response. Faseb J 18:816-27
80.Odekon LE, Blasi F, Rifkin DB 1994 Requirement for receptor-bound urokinase in plasmin-dependent cellular conversion of latent TGF-beta to TGF-beta. J Cell Physiol 158:398-407
81.Li YY, McTiernan CF, Feldman AM 2000 Interplay of matrix metalloproteinases, tissue inhibitors of metalloproteinases and their regulators in cardiac matrix remodeling. Cardiovasc Res 46:214-24
82.Gallagher GL, Jackson CJ, Hunyor SN 2007 Myocardial extracellular matrix remodeling in ischemic heart failure. Front Biosci 12:1410-9
83.Ramos-DeSimone N, Hahn-Dantona E, Sipley J, Nagase H, French DL, Quigley JP 1999 Activation of matrix metalloproteinase-9 (MMP-9) via a converging plasmin/stromelysin-1 cascade enhances tumor cell invasion. J Biol Chem 274:13066-76
84. Chang MH, Kuo WW, Chen RJ, Lu MC, Tsai FJ, Kuo WH, Chen LY, Wu WJ, Huang CY, Chu CH 2008 IGF-II/mannose 6-phosphate receptor activation induces metalloproteinase-9 matrix activity and increases plasminogen activator expression in H9c2 cardiomyoblast cells. J Mol Endocrinol 41:65-74
85.Barlow DP, Stoger R, Herrmann BG, Saito K, Schweifer N 1991 The mouse insulin-like growth factor type-2 receptor is imprinted and closely linked to the Tme locus. Nature 349:84-7
86.Wutz A, Barlow DP 1998 Imprinting of the mouse Igf2r gene depends on an intronic CpG island. Mol Cell Endocrinol 140:9-14
87.Vu TH, Li T, Hoffman AR 2004 Promoter-restricted histone code, not the differentially methylated DNA regions or antisense transcripts, marks the imprinting status of IGF2R in human and mouse. Hum Mol Genet 13:2233-45
88.Hu JF, Pham J, Dey I, Li T, Vu TH, Hoffman AR 2000 Allele-specific histone acetylation accompanies genomic imprinting of the insulin-like growth factor II receptor gene. Endocrinology 141:4428-35
89.Yang Y, Li T, Vu TH, Ulaner GA, Hu JF, Hoffman AR 2003 The histone code regulating expression of the imprinted mouse Igf2r gene. Endocrinology 144:5658-70
90.Weiner JA, Chen A, Davis BH 1998 E-box-binding repressor is down-regulated in hepatic stellate cells during up-regulation of mannose 6-phosphate/insulin-like growth factor-II receptor expression in early hepatic fibrogenesis. J Biol Chem 273:15913-9
91.Weiner JA, Chen A, Davis BH 2000 Platelet-derived growth factor is a principal inductive factormodulating mannose 6-phosphate/insulin-like growth factor-II receptorgene expression via a distal E-box in activated hepatic stellate cells. Biochem J 345 Pt 2:225-31
92.Morimoto T, Sunagawa Y, Kawamura T, Takaya T, Wada H, Nagasawa A, Komeda M, Fujita M, Shimatsu A, Kita T, Hasegawa K 2008 The dietary compound curcumin inhibits p300 histone acetyltransferase activity and prevents heart failure in rats. J Clin Invest 118:868-78
93.Li HL, Liu C, de Couto G, Ouzounian M, Sun M, Wang AB, Huang Y, He CW, Shi Y, Chen X, Nghiem MP, Liu Y, Chen M, Dawood F, Fukuoka M, Maekawa Y, Zhang L, Leask A, Ghosh AK, Kirshenbaum LA, Liu PP 2008 Curcumin prevents and reverses murine cardiac hypertrophy. J Clin Invest 118:879-93
94.Xing Y, Lee C 2007 Relating alternative splicing to proteome complexity and genome evolution. Adv Exp Med Biol 623:36-49
95.Wheeler DL, Church DM, Federhen S, Lash AE, Madden TL, Pontius JU, Schuler GD, Schriml LM, Sequeira E, Tatusova TA, Wagner L 2003 Database resources of the National Center for Biotechnology. Nucleic Acids Res 31:28-33
96.Spicer LJ, Aad PY 2007 Insulin-like growth factor (IGF) 2 stimulates steroidogenesis and mitosis of bovine granulosa cells through the IGF1 receptor: role of follicle-stimulating hormone and IGF2 receptor. Biol Reprod 77:18-27
97.Pavelic J, Radakovic B, Pavelic K 2007 Insulin-like growth factor 2 and its receptors (IGF 1R and IGF 2R/mannose 6-phosphate) in endometrial adenocarcinoma. Gynecol Oncol 105:727-35
98.Kar S, Seto D, Dore S, Hanisch U, Quirion R 1997 Insulin-like growth factors-I and -II differentially regulate endogenous acetylcholine release from the rat hippocampal formation. Proc Natl Acad Sci U S A 94:14054-9
99.Sferruzzi-Perri AN, Owens JA, Pringle KG, Robinson JS, Roberts CT 2006 Maternal insulin-like growth factors-I and -II act via different pathways to promote fetal growth. Endocrinology 147:3344-55
100.Olson EN, Schneider MD 2003 Sizing up the heart: development redux in disease. Genes Dev 17:1937-56
101.Bonifacino JS, Traub LM 2003 Signals for sorting of transmembrane proteins to endosomes and lysosomes. Annu Rev Biochem 72:395-447
102.Saeki H, Hamada M, Hiwada K 2002 Circulating levels of insulin-like growth factor-1 and its binding proteins in patients with hypertrophic cardiomyopathy. Circ J 66:639-44
103.Korner C, Nurnberg B, Uhde M, Braulke T 1995 Mannose 6-phosphate/insulin-like growth factor II receptor fails to interact with G-proteins. Analysis of mutant cytoplasmic receptor domains. J Biol Chem 270:287-95
104.Lezoualc''h F, Metrich M, Hmitou I, Duquesnes N, Morel E 2008 Small GTP-binding proteins and their regulators in cardiac hypertrophy. J Mol Cell Cardiol 44:623-32
105.Bers DM 2008 Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol 70:23-49
106.Molkentin JD 2006 Dichotomy of Ca2+ in the heart: contraction versus intracellular signaling. J Clin Invest 116:623-6
107.Ter Keurs HE, Boyden PA 2007 Calcium and arrhythmogenesis. Physiol Rev 87:457-506
108.Chakraborti S, Das S, Kar P, Ghosh B, Samanta K, Kolley S, Ghosh S, Roy S, Chakraborti T 2007 Calcium signaling phenomena in heart diseases: a perspective. Mol Cell Biochem 298:1-40
109.Braz JC, Gregory K, Pathak A, Zhao W, Sahin B, Klevitsky R, Kimball TF, Lorenz JN, Nairn AC, Liggett SB, Bodi I, Wang S, Schwartz A, Lakatta EG, DePaoli-Roach AA, Robbins J, Hewett TE, Bibb JA, Westfall MV, Kranias EG, Molkentin JD 2004 PKC-alpha regulates cardiac contractility and propensity toward heart failure. Nat Med 10:248-54
110.Wu G, Toyokawa T, Hahn H, Dorn GW, 2nd 2000 Epsilon protein kinase C in pathological myocardial hypertrophy. Analysis by combined transgenic expression of translocation modifiers and Galphaq. J Biol Chem 275:29927-30
111.Ronkainen JJ, Vuolteenaho O, Tavi P 2007 Calcium-calmodulin kinase II is the common factor in calcium-dependent cardiac expression and secretion of A- and B-type natriuretic peptides. Endocrinology 148:2815-20
112.Vila-Petroff M, Salas MA, Said M, Valverde CA, Sapia L, Portiansky E, Hajjar RJ, Kranias EG, Mundina-Weilenmann C, Mattiazzi A 2007 CaMKII inhibition protects against necrosis and apoptosis in irreversible ischemia-reperfusion injury. Cardiovasc Res 73:689-98
113.Bers DM 2006 Altered cardiac myocyte Ca regulation in heart failure. Physiology (Bethesda) 21:380-7
114.Matsui T, Nagoshi T, Rosenzweig A 2003 Akt and PI 3-kinase signaling in cardiomyocyte hypertrophy and survival. Cell Cycle 2:220-3
115.Vega RB, Bassel-Duby R, Olson EN 2003 Control of cardiac growth and function by calcineurin signaling. J Biol Chem 278:36981-4
116.Kuo WW, Wu CH, Lee SD, Lin JA, Chu CY, Hwang JM, Ueng KC, Chang MH, Yeh YL, Wang CJ, Liu JY, Huang CY 2005 Second-hand smoke-induced cardiac fibrosis is related to the Fas death receptor apoptotic pathway without mitochondria-dependent pathway involvement in rats. Environ Health Perspect 113:1349-53
117.Kass DA, Bronzwaer JG, Paulus WJ 2004 What mechanisms underlie diastolic dysfunction in heart failure? Circ Res 94:1533-42
118.Jong GP, Ma T, Chou P, Chang MH, Wu CH, Lis PC, Lee SD, Liu JY, Kuo WW, Huang CY 2006 Serum MMP-9 activity as a diagnosing marker for the developing heart failure of post MI patients. Chin J Physiol 49:104-9
119.Jong GP, Wang YF, Tsai FJ, Tsai CH, Wu CL, Liu RH, Hsieh DJ, Ko FY, Huang CY, Lee SD 2007 Immunoglobulin E and matrix metalloproteinase-9 in patients with different stages of coronary artery diseases. Chin J Physiol 50:277-82
120.Vu TH, Jirtle RL, Hoffman AR 2006 Cross-species clues of an epigenetic imprinting regulatory code for the IGF2R gene. Cytogenet Genome Res 113:202-8
121.McKinsey TA, Olson EN 2004 Cardiac histone acetylation--therapeutic opportunities abound. Trends Genet 20:206-13
122.Olson EN, Backs J, McKinsey TA 2006 Control of cardiac hypertrophy and heart failure by histone acetylation/deacetylation. Novartis Found Symp 274:3-12; discussion 13-9, 152-5, 272-6
123.Margueron R, Trojer P, Reinberg D 2005 The key to development: interpreting the histone code? Curr Opin Genet Dev 15:163-76
124.Morimoto RI 1993 Cells in stress: transcriptional activation of heat shock genes. Science 259:1409-10
125.Liberek K, Lewandowska A, Zietkiewicz S 2008 Chaperones in control of protein disaggregation. Embo J 27:328-35
126.Date T, Mochizuki S, Belanger AJ, Yamakawa M, Luo Z, Vincent KA, Cheng SH, Gregory RJ, Jiang C 2005 Expression of constitutively stable hybrid hypoxia-inducible factor-1alpha protects cultured rat cardiomyocytes against simulated ischemia-reperfusion injury. Am J Physiol Cell Physiol 288:C314-20
127. Chi NC, Karliner JS 2004 Molecular determinants of responses to myocardial ischemia/reperfusion injury: focus on hypoxia-inducible and heat shock factors. Cardiovasc Res 61:437-47
128.Toko H, Minamino T, Komuro I 2008 Role of heat shock transcriptional factor 1 and heat shock proteins in cardiac hypertrophy. Trends Cardiovasc Med 18:88-93
129. Sakamoto M, Minamino T, Toko H, Kayama Y, Zou Y, Sano M, Takaki E, Aoyagi T, Tojo K, Tajima N, Nakai A, Aburatani H, Komuro I 2006 Upregulation of heat shock transcription factor 1 plays a critical role in adaptive cardiac hypertrophy. Circ Res 100(3):e45-6.


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