進階搜尋


下載電子全文  
系統識別號 U0026-1505201323074000
論文名稱(中文) 胰島素受體受質和疾病及致病機制關聯性之探討
論文名稱(英文) Investigation of the association of insulin receptor substrates with diseases and relevant pathogenesis
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 101
學期 2
出版年 102
研究生(中文) 詹世鴻
研究生(英文) Shih-Hung Chan
學號 s98921034
學位類別 博士
語文別 英文
論文頁數 113頁
口試委員 指導教授-陳志鴻
指導教授-張文昌
口試委員-林幸榮
口試委員-許惠恆
口試委員-李貽恆
口試委員-蔡曜聲
中文關鍵字 胰島素受體受質  氧化壓力  活性氧  自噬作用  癌症  冠狀動脈疾病  自噬作用相關基因  rapamycin  atorvastatin  血管平滑肌細胞  單一核苷酸多形性變異 
英文關鍵字 insulin receptor substrate  oxidative stress  reactive oxygen species  autophagy  cancer  coronary artery disease  autophagy related gene  rapamycin  atorvastatin  vascular smooth muscle cell  single nucleotide polymorphism 
學科別分類
中文摘要 雖然胰島素受體受質本身不具蛋白酶活性,但它可以和數種結合蛋白或蛋白酶結合,負責傳遞胰島素或類胰島素生長因子的訊息至細胞內,影響細胞內的訊息傳遞及調節細胞功能。已有些研究結果指出,胰島素受體受質和癌症及冠狀動脈疾病有關聯性存在。在某些癌症細胞中,第一型及第二型胰島素受體受質的表現量有增加的情形。抑制第一型胰島素受體受質的表現量,可以增加抗癌藥物的效果;相反地,在癌細胞中過度表現第一型胰島素受體受質,則會增加癌細胞的抗藥性。在第一型及第二型胰島素受體受質基因的去氧核糖核苷酸上存在的單一核苷酸多形性變異,已被發現和個體罹患冠狀動脈疾病的機率有相關性存在。此外,在冠狀動脈粥狀硬化瘢塊中的脂中心處,可見到第一型胰島素受體受質的大量表現。個體周邊血液中巨噬球中的第二型胰島素受體受質表現量愈高,個體罹患冠狀動脈疾病的機率愈高。

Gly1057Asp多形性變化是第二型胰島素受體受質上一個常見由單一核苷酸多形性變異所造成的基因變異,這個基因變異已被發現和胰島素抵抗性及糖尿病的發生有關。因為胰島素抵抗性及糖尿病二者皆是造成冠狀動脈疾病的重要危險因子,因此個人假設第二型胰島素受體受質上的Gly1057Asp多形性變化和個體罹患冠狀動脈疾病的機率有關。在我的研究中發現,若個體之第二型胰島素受體受質基因上第1057個位置上的氨基酸若為甘氨酸(Gly),則個體罹患冠狀動脈疾病的機率較不含甘氨酸的個體為高。此外,就冠狀動脈疾病的致病性而言,甘氨酸及糖尿病所造成的影響具相加性,意即個體若同時具有甘氨酸及罹患糖尿病,則此個體得到冠狀動脈疾病的機率較其他族群高出許多。

癌症及冠狀動脈疾病在就細胞惡性度而言,雖為不同類疾病,但這兩個疾病之間卻有其共通性存在。其一,這兩個疾病的組成細胞都有細胞生長及增生速度增加的情形。其二,這兩個疾病都和活性氧 (reactive oxygen species)及氧化壓力 (oxidative stress) 有關。低濃度的活性氧可以促進癌症細胞生長及增生,但高濃度的活性氧則會造成癌症細胞死亡。活性氧會引發血管內皮細胞功能異常,而血管內皮細胞功能異常會造成動脈之粥狀硬化。其三,癌症及冠狀動脈疾病都和細胞自噬作用相關。細胞自噬作用是細胞內存在的一種機制,可以協助細胞面對外在壓力,使細胞能存活下來。在癌症細胞及在冠狀動脈粥狀硬化瘢塊中的脂中心處,第一型胰島素受體受質的表現量增加的原因至今未被完全明瞭。因此,在我的研究中嘗試去探討這個議題。我從探討第一型胰島素受體受質、氧化壓力及細胞自噬作用彼此之間的關聯性切入,除了研究它們對細胞死亡的影響,也特別研究它們對存在於癌症及冠狀動脈疾病間共同及重要的現象,意即細胞生長及增生速度增加的影響。我發現第一型胰島素受體受質的過度表現可以促進細胞增生、抑制自噬作用、減低氧化壓力所誘發的細胞自噬作用以及減少藉由氧化壓力所造成的自噬作用型細胞死亡(autophagic cell death)。因此,我們認為第一型胰島素受體受質可以促進細胞生長及增生,也可以協助細胞抵抗在細胞生長及增生中大量增加之活性氧的細胞毒性而得以繼續增生及生長下去。另外,我也發現壓抑自噬作用相關第五基因可以抑制自噬作用、減低小鼠主動脈血管平滑肌細胞增生及加強rapamycin及atorvastatin抑制小鼠主動脈血管平滑肌細胞增生的能力。因此,我認為自噬作用相關第五基因和小鼠主動脈血管平滑肌細胞的增生能力有關;因為rapamycin及atorvastatin會促進自噬作用,而自噬作用通常為細胞應付外在壓力的存活機制,我認為藉由壓抑自噬作用相關第五基因可以減低這種存活機制的影響,而提高 rapamycin及atorvastatin抑制小鼠主動脈血管平滑肌細胞增生的能力。再者,我在研究中指出,壓抑自噬作用相關第五基因會減少Akt,p70 S6K,及ERK的活性;而Akt,p70 S6K,及ERK的活性皆受到胰島素及第一型胰島素受體受質的訊息所調控,因此,自噬作用相關第五基因可能也會和胰島素及第一型胰島素受體受質的訊息調控有關。
英文摘要 Although insulin receptor substrate (IRS) has no intrinsic kinase activity, it serves as an adaptor protein to organize protein complexes and to transmit the signals mainly from insulin and insulin-like growth factor to affect downstream signals and regulate cellular functions. There have been several lines of evidence revealing that IRS is linked to cancer and coronary artery disease (CAD). The expression level of IRS-1 and IRS-2 is elevated in several human cancers. Suppression of IRS-1 enhances the effects of anticancer medications and overexpression of IRS-1 renders cancer cells resistant to anti-cancer therapy. Single nucleotide polymorphism (SNP) in the coding region of IRS-1 gene and the promoter region in IRS-2 gene is associated with risk of CAD. IRS-1 is abundantly expressed in the lipid core of atherosclerotic plaque. Level of IRS-2 in macrophages is positively correlated with individual’s susceptibility to CAD.

Gly1057Asp polymorphism in IRS-2, caused by a SNP, is commonly seen and associated with insulin resistance and diabetes mellitus (DM). Because insulin resistance and DM are potent risk factors for CAD, it is possible that Gly1057Asp polymorphism in IRS-2 is associated with the susceptibility of CAD. In investigating the association between the Gly1057Asp polymorphism in IRS-2 with risk of CAD, I found that the Gly allele at codon 1057 of IRS-2 gene is associated with an increased risk of CAD. Additionally, I found that there is a synergistic effect toward CAD between pathogenicity of DM and that of the Gly allele.

Cancer is a malignant disease, but CAD is not. However, both cancer and CAD share several similarities. First, cell growth and proliferation rates increase in both diseases. Second, reactive oxygen species (ROS) and oxidative stress contribute to the pathogenesis of cancer and CAD. It has been shown that low-level ROS promotes cell growth and proliferation but high-level ROS kills cancer cells. ROS leads to endothelial dysfunction that has been shown to promote de novo atherosclerosis. Third, both cancer and CAD are associated with autophagy, which is generally thought to be a survival mechanism for cells in response to external stimuli. The reasons for increased expression levels of IRS-1 in cancer cells and the lipid core of atherosclerotic plaques are not completely understood. I investigated the interrelation between IRS-1, oxidative stress, and autophagy with a focus on evaluation of their influence on cell death as well as the key and common feature of cancer and atherosclerosis, increased cell growth and proliferation. I found that overexpression of IRS-1 promotes cells growth, inhibits basal autophagy, reduces oxidative stress-induced autophagy, and diminishes oxidative stress-mediated autophagy-dependent cell death. I conclude that IRS-1 can promote cell proliferation and help cells to resist the cytotoxic effects of oxidative stress that is generated during cell growth and proliferation. Additionally, I also demonstrated that knockdown of autophagy related gene 5 (ATG-5) inhibits autophagy, reduces the basal cell proliferation rate in mouse aortic vascular smooth muscle cells (VSMCs), and enhances the antiproliferative effects of rapamycin and atorvastatin, which are known to promote autophagy induction. I conclude that ATG-5 is essential for basal cell growth and that inhibition of ATG-5 and autophagy can enhance the effects of antiproliferative medications. Moreover, I demonstrated that knockdown of ATG-5 attenuates the activity of Akt, p70 S6K, and ERK. Because Akt, p70 S6K, and ERK are all affected by the insulin/IRS-1 signaling, it is possible that ATG-5 may contribute to the regulation of insulin/IRS-1 signaling.
論文目次 Contents

Chapter 1. Introduction……………………………………...….…….………………1

1.1 Insulin receptor substrate……………………………….……………….3

1.1.1 Insulin receptor substrate family……………………….………….3

1.1.2 Transmission of insulin and IGF signaling by insulin receptor

substrate…………………………………………………………...5

1.1.3 Insulin resistance and cell proliferation…………….……………..8

1.1.4 Insulin receptor substrate and cancer……………………………...8

1.1.5 Insulin receptor substrate and coronary artery disease….……..…10

1.2 Oxidative stress…………………………………………...……………12

1.2.1 Introduction of oxidative stress…………………………………..12

1.2.2 Oxidative stress and cancer………………………………………13

1.2.3 Oxidative stress and coronary artery disease…………………….14

1.2.4 Oxidative stress and insulin receptor substrate-1 signaling……...15

1.2.5 Oxidative stress and cell death………………...…………………15

1.3 Autophagy……………………………………………………...………16

1.3.1 Function and regulation of autophagy……………………………16

1.3.2 Autophagy and cancer……………………………………………17

1.3.3 Autophagy and coronary artery disease………………………….18

1.3.4 Autophagy and oxidative stress…………………………………..20

1.4 Thesis aims……………………………………………………………..22

Chapter 2. Association between Gly1057Asp polymorphism of insulin receptor

substrate-2 and coronary artery disease in the Taiwanese population…..25

2.1 Background and Aims………………………………..….…….………25

2.2 Methods……………………….……...………………...……………...27

2.3 Results…………………………….……………………..…………….31

2.4 Discussion……….………………………………………..…………...34

2.5 Conclusions………….…………………………………..…………….37

2.6 Tables……………….…………………………………..……………..38

2.7 Figures…………….…………………………………………..……….44

2.8 Appendix………………………….…………………………..……….45

Chapter 3. Investigation of interrelation between insulin receptor substrate-1,

oxidative stress, and autophagy in pathophysiology of human diseases...47

3.1 Background and Aims…….………………………………………...….47

3.2 Materials and Methods……….………………………...………………49

3.3 Results……………….……...………………………………………….55

3.4 Discussion……….………………………………...…………………...66

3.5 Conclusion……………………………………………………………...72

3.6 Figures……………….……………………………...………………….74

Chapter 4. General discussion, Conclusion, and Prospects…………………………..91

Bibliography…………………………………………………………………..……...95

參考文獻 1. White M, Maron R, Kahn C: Insulin rapdly stimulates
tyrosine phosphorylation of a Mr-185,000 protein in intact
cells. Nature 1985, 318:183-186.
2. Sun XJ, Rothenberg P, Kahn CR, Backer JM, Araki E,
Wilden PA, Cahill DA, Goldstein BJ, White MF: Structure of
the insulin receptor substrate IRS-1 defines a unique signal
transduction protein. Nature 1991, 352(6330):73-77.
3. Araki E, Lipes MA, Patti ME, Bruning JC, Haag B, 3rd,
Johnson RS, Kahn CR: Alternative pathway of insulin
signalling in mice with targeted disruption of the IRS-1
gene. Nature 1994, 372(6502):186-190.
4. Sun XJ, Wang LM, Zhang Y, Yenush L, Myers MG, Jr.,
Glasheen E, Lane WS, Pierce JH, White MF: Role of IRS-2 in
insulin and cytokine signalling. Nature 1995,
377(6545):173-177.
5. Bernal D, Almind K, Yenush L, Ayoub M, Zhang Y, Rosshani
L, Larsson C, Pedersen O, White MF: Insulin receptor
substrate-2 amino acid polymorphisms are not associated
with random type 2 diabetes among Caucasians.
Diabetes 1998, 47(6):976-979.
6. Uchida T, Myers MG, White MF: IRS-4 Mediates Protein
Kinase B Signaling during Insulin Stimulation without
Promoting Antiapoptosis. Mol Cell Biol 2000, 20(1):126-138.
7. Previs SF, Withers DJ, Ren JM, White MF, Shulman GI:
Contrasting effects of IRS-1 versus IRS-2 gene disruption on
carbohydrate and lipid metabolism in vivo. J Biol Chem
2000, 275(50):38990-38994.
8. Grimm J, Sachs M, Britsch S, Di Cesare S, Schwarz-Romond T, Alitalo K, Birchmeier W: Novel p62dok family members, dok-4 and dok-5, are substrates of the c-Ret receptor tyrosine kinase and mediate neuronal differentiation. J Cell Biol 2001, 154(2):345-354.
9. Favre C, Gerard A, Clauzier E, Pontarotti P, Olive D, Nunes JA: DOK4 and DOK5: new Dok-related genes expressed in human T cells. Genes Immun 2003, 4(1):40-45.
10. Cai D, Dhe-Paganon S, Melendez PA, Lee J, Shoelson SE: Two new substrates in insulin signaling, IRS5/DOK4 and IRS6/DOK5. J Biol Chem 2003, 278(28):25323-25330.
11. White MF: IRS proteins and the common path to diabetes. Am J Physiol Endocrinol Metab 2002, 283(3):E413-422.
12. Burks DJ, Pons S, Towery H, Smith-Hall J, Myers MG, Jr., Yenush L, White MF: Heterologous pleckstrin homology domains do not couple IRS-1 to the insulin receptor. J Biol Chem 1997, 272(44):27716-27721.
13. Yenush L, Zanella C, Uchida T, Bernal D, White MF: The pleckstrin homology and phosphotyrosine binding domains of insulin receptor substrate 1 mediate inhibition of apoptosis by insulin. Mol Cell Biol 1998, 18(11):6784-6794.
14. Lee CH, Li W, Nishimura R, Zhou M, Batzer AG, Myers MG, Jr., White MF, Schlessinger J, Skolnik EY: Nck Associates with the SH2 Domain-Docking Protein IRS-1 in Insulin- Stimulated Cells. Proc Natl Acad Sci U S A 1993, 90(24):11713-11717.
15. Myers MG, Grammer TC, Wang LM, Sun XJ, Pierce JH, Blenis J, White MF: Insulin receptor substrate-1 mediates phosphatidylinositol 3'-kinase and p70S6k signaling during insulin, insulin-like growth factor-1, and interleukin-4 stimulation. J Biol Chem 1994, 269(46):28783-28789.
16. Myers MG, Wang LM, Sun XJ, Zhang Y, Yenush L, Schlessinger J, Pierce JH, White MF: Role of IRS-1-GRB-2 complexes in insulin signaling. Mol Cell Biol 1994, 14(6):3577-3587.
17. Beitner-Johnson D, Blakesley VA, Shen-Orr Z, Jimenez M, Stannard B, Wang L-M, Pierce J, LeRoith D: The Proto-oncogene Product c-Crk Associates with Insulin Receptor Substrate-1 and 4PS. J Biol Chem 1996, 271(16):9287-9290.
18. Myers MG, Mendez R, Shi P, Pierce JH, Rhoads R, White MF: The COOH-terminal Tyrosine Phosphorylation Sites on IRS-1 Bind SHP-2 and Negatively Regulate Insulin Signaling. J Biol Chem 1998, 273(41):26908-26914.
19. Wu J, Tseng YD, Xu CF, Neubert TA, White MF, Hubbard SR: Structural and biochemical characterization of the KRLB region in insulin receptor substrate-2. Nat Struct Mol Biol 2008, 15(3):251-258.
20. Shaw LM: The insulin receptor substrate (IRS) proteins: at the intersection of metabolism and cancer. Cell Cycle 2011, 10(11):1750-1756.
21. Tamemoto H, Kadowaki T, Tobe K, Yagi T, Sakura H, Hayakawa T, Terauchi Y, Ueki K, Kaburagi Y, Satoh S et al: Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Nature 1994, 372(6502):182-186.
22. Withers DJ, Gutierrez JS, Towery H, Burks DJ, Ren JM, Previs S, Zhang Y, Bernal D, Pons S, Shulman GI et al: Disruption of IRS-2 causes type 2 diabetes in mice. Nature 1998, 391(6670):900-904.
23. Schubert M, Brazil DP, Burks DJ, Kushner JA, Ye J, Flint CL, Farhang-Fallah J, Dikkes P, Warot XM, Rio C et al: Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation. J Neurosci 2003, 23(18):7084-7092.
24. Withers DJ, Burks DJ, Towery HH, Altamuro SL, Flint CL, White MF: Irs-2 coordinates Igf-1 receptor-mediated beta-cell development and peripheral insulin signalling. Nat Genet 1999, 23(1):32-40.
25. Belfiore A, Malaguarnera R: Insulin receptor and cancer. Endocr Relat Cancer 2011, 18(4):11-0074.
26. Jiang ZY, Lin YW, Clemont A, Feener EP, Hein KD, Igarashi M, Yamauchi T, White MF, King GL: Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats. J Clin Invest 1999, 104(4):447-457.
27. Cusi K, Maezono K, Osman A, Pendergrass M, Patti ME, Pratipanawatr T, DeFronzo RA, Kahn CR, Mandarino LJ: Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. J Clin Invest 2000, 105(3):311-320.
28. Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, Pollak M, Regensteiner JG, Yee D: Diabetes and cancer: a consensus report. CA Cancer J Clin 2010, 60(4):207-221.
29. Pollak M: Insulin and insulin-like growth factor signalling in neoplasia. Nat Reviews Cancer 2008, 8(12):915-928.
30. Bergmann U, Funatomi H, Kornmann M, Beger HG, Korc M: Increased Expression of Insulin Receptor Substrate-1 in Human Pancreatic Cancer. Biochem Biophys Res Commun 1996, 220(3):886-890.
31. Kornmann M, Maruyama H, Bergmann U, Tangvoranuntakul P, Beger HG, White MF, Korc M: Enhanced Expression of the Insulin Receptor Substrate-2 Docking Protein in Human Pancreatic Cancer. Cancer Res 1998, 58(19):4250-4254.
32. Hellawell GO, Turner GDH, Davies DR, Poulsom R, Brewster SF, Macaulay VM: Expression of the Type 1 Insulin-like Growth Factor Receptor Is Up-Regulated in Primary Prostate Cancer and Commonly Persists in Metastatic Disease. Cancer Res 2002, 62(10):2942-2950.
33. Rocha RL, Hilsenbeck SG, Jackson JG, VanDenBerg CL, Weng Cn, Lee AV, Yee D: Insulin-like growth factor binding protein-3 and insulin receptor substrate-1 in breast cancer: correlation with clinical parameters and disease-free survival. Clin Cancer Res 1997, 3(1):103-109.
34. Koda M, Sulkowska M, Kanczuga-Koda L, Sulkowski S: Expression of insulin receptor substrate 1 in primary breast cancer and lymph node metastases. J Clin Pathol 2005, 58(6):645-649.
35. Ravikumar S, Perez-Liz G, Del Vale L, Soprano DR, Soprano KJ: Insulin Receptor Substrate-1 Is an Important Mediator of Ovarian Cancer Cell Growth Suppression by All-trans Retinoic Acid. Cancer Res 2007, 67(19):9266-9275.
36. Mardilovich K, Pankratz S, Shaw L: Expression and function of the insulin receptor substrate proteins in cancer. Cell Commun Signal 2009, 7(1):14.
37. Nolan MK, Jankowska L, Prisco M, Xu S, Guvakova MA, Surmacz E: Differential roles of IRS-1 and SHC signaling pathways in breast cancer cells. Int J Cancer 1997, 72(5):828-834.
38. Jackson JG, White MF, Yee D: Insulin Receptor Substrate-1 is the Predominant Signaling Molecule Activated by Insulin-like Growth Factor-I, Insulin, and Interleukin-4 in Estrogen Receptor-positive Human Breast Cancer Cells. J Biol Chem 1998, 273(16):9994-10003.
39. Taouis M, Dupont J, Gillet A, Derouet M, Simon J: Insulin receptor substrate 1 antisense expression in an hepatoma cell line reduces cell proliferation and induces overexpression of the Src homology 2 domain and collagen protein (SHC). Mol Cell Endocrinol 1998, 137(2):177-186.
40. Wang JY, Del Valle L, Gordon J, Rubini M, Romano G, Croul S, Peruzzi F, Khalili K, Reiss K: Activation of the IGF-IR system contributes to malignant growth of human and mouse medulloblastomas. Oncogene 2001, 20(29):3857.
41. Hoang CD, Zhang X, Scott PD, Guillaume TJ, Maddaus MA, Yee D, Kratzke RA: Selective activation of insulin receptor substrate-1 and -2 in pleural mesothelioma cells: association with distinct malignant phenotypes. Cancer Res 2004, 64(20):7479-7485.
42. Cesarone G, Garofalo C, Abrams MT, Igoucheva O, Alexeev V, Yoon K, Surmacz E, Wickstrom E: RNAi-mediated silencing of insulin receptor substrate 1 (IRS-1) enhances tamoxifen-induced cell death in MCF-7 breast cancer cells. J Cell Biochem 2006, 98(2):440-450.
43. Tanaka S, Wands JR: Insulin receptor substrate 1 overexpression in human hepatocellular carcinoma cells prevents transforming growth factor beta1-induced apoptosis. Cancer Res 1996, 56(15):3391-3394.
44. Dearth RK, Cui X, Kim H-J, Kuiatse I, Lawrence NA, Zhang X, Divisova J, Britton OL, Mohsin S, Allred DC et al: Mammary Tumorigenesis and Metastasis Caused by Overexpression of Insulin Receptor Substrate 1 (IRS-1) or IRS-2. Mol Cell Biol 2006, 26(24):9302-9314.
45. Schnarr B, Strunz K, Ohsam J, Benner A, Wacker J, Mayer D: Down-regulation of insulin-like growth factor-I receptor and insulin receptor substrate-1 expression in advanced human breast cancer. Int J Cancer 2000, 89(6):506-513.
46. Sisci D, Morelli C, Garofalo C, Romeo F, Morabito L, Casaburi F, Middea E, Cascio S, Brunelli E, Ando S et al: Expression of nuclear insulin receptor substrate 1 in breast cancer. J Clin Pathol 2007, 60(6):633-641.
47. Gual P, Le Marchand-Brustel Y, Tanti JF: Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. Biochimie 2005, 87(1):99-109.
48. Boissan M, Beurel E, Wendum D, Rey C, Lecluse Y, Housset C, Lacombe ML, Desbois-Mouthon C: Overexpression of insulin receptor substrate-2 in human and murine hepatocellular carcinoma. Am J Pathol 2005, 167(3):869-877.
49. Szabolcs M, Keniry M, Simpson L, Reid LJ, Koujak S, Schiff SC, Davidian G, Licata S, Gruvberger-Saal S, Murty VV et al: Irs2 inactivation suppresses tumor progression in Pten+/- mice. Am J Pathol 2009, 174(1):276-286.
50. Ross R: Atherosclerosis--an inflammatory disease. N Engl J Med 1999, 340(2):115-126.
51. Braunwald's heart disease: a text book of cardiovascular medicine, 8th edn. Philadelphia, PA, USA: Saunders Elsevier; 2008.
52. Benditt EP, Benditt JM: Evidence for a monoclonal origin of human atherosclerotic plaques. Proc Natl Acad Sci U S A 1973, 70(6):1753-1756.
53. Schwartz SM, Murry CE: Proliferation and the monoclonal origins of atherosclerotic lesions. Annu Rev Med 1998, 49:437-460.
54. Ardestani SK, Inserra P, Solkoff D, Watson RR: The role of cytokines and chemokines on tumor progression: A review. Cancer Detect Prev 1999, 23(3):215-225.
55. Gerszten RE, Mach F, Sauty A, Rosenzweig A, Luster AD: Chemokines, leukocytes, and atherosclerosis. J Lab Clin Med 2000, 136(2):87-92.
56. Chang BD, Watanabe K, Broude EV, Fang J, Poole JC, Kalinichenko TV, Roninson IB: Effects of p21Waf1/Cip1/Sdi1 on cellular gene expression: implications for carcinogenesis, senescence, and age-related diseases. Proc Natl Acad Sci U S A 2000, 97(8):4291-4296.
57. Newby AC, Zaltsman AB: Molecular mechanisms in intimal hyperplasia. J Pathol 2000, 190(3):300-309.
58. Sanz-Gonzalez SM, Poch E, Perez-Roger I, Diez-Juan A, Ivorra C, Andres V: Control of vascular smooth muscle cell growth by cyclin-dependent kinase inhibitory proteins and its implication in cardiovascular disease. Front Biosci 2000, 1(5):D619-628.
59. Zettler ME, Pierce GN: Cell cycle proteins and atherosclerosis. Herz 2000, 25(2):100-107.
60. Jimenez-Navarro MF, Bueno H, Alvarez-Sala L, Rodriguez-Losada N, Andres V, Gonzalez-Navarro H: Insulin receptor substrate-1 expression is increased in circulating leukocytes of patients with acute coronary syndrome. ISRN Cardiol 2011, 740585(10):16.
61. Baroni MG, D'Andrea MP, Montali A, Pannitteri G, Barilla F, Campagna F, Mazzei E, Lovari S, Seccareccia F, Campa PP et al: A common mutation of the insulin receptor substrate-1 gene is a risk factor for coronary artery disease. Arterioscler Thromb Vasc Biol 1999, 19(12):2975-2980.
62. Morgan TM, Xiao L, Lyons P, Kassebaum B, Krumholz HM, Spertus JA: Investigation of 89 candidate gene variants for effects on all-cause mortality following acute coronary syndrome. BMC Med Genet 2008, 9(66):1471-2350.
63. Hagg DA, Jernas M, Wiklund O, Thelle DS, Fagerberg B, Eriksson P, Hamsten A, Olsson B, Carlsson B, Carlsson LM et al: Expression profiling of macrophages from subjects with atherosclerosis to identify novel susceptibility genes. Int J Mol Med 2008, 21(6):697-704.
64. Thannickal VJ, Fanburg BL: Reactive oxygen species in cell signaling. Am J Physiol Lung Cell Mol Physiol 2000, 279(6):L1005-1028.
65. Freeman BA, Crapo JD: Biology of disease: free radicals and tissue injury. Lab Invest 1982, 47(5):412-426.
66. Pryor WA, Houk KN, Foote CS, Fukuto JM, Ignarro LJ, Squadrito GL, Davies KJA: Free radical biology and medicine: it's a gas, man! Am J Physiol Regul Integr Comp Physiol 2006, 291(3):R491-R511.
67. Martindale JL, Holbrook NJ: Cellular response to oxidative stress: Signaling for suicide and survival*. J Cell Physiol 2002, 192(1):1-15.
68. Ames BN: Dietary carcinogens and anticarcinogens. Oxygen radicals and degenerative diseases. Science 1983, 221(4617):1256-1264.
69. Loft S, Poulsen HE: Cancer risk and oxidative DNA damage in man. J Mol Med (Berl) 1996, 74(6):297-312.
70. Higinbotham KG, Rice JM, Diwan BA, Kasprzak KS, Reed CD, Perantoni AO: GGT to GTT transversions in codon 12 of the K-ras oncogene in rat renal sarcomas induced with nickel subsulfide or nickel subsulfide/iron are consistent with oxidative damage to DNA. Cancer Res 1992, 52(17):4747-4751.
71. Denissenko MF, Venkatachalam S, Ma YH, Wani AA: Site-specific induction and repair of benzo[a]pyrene diol epoxide DNA damage in human H-ras protooncogene as revealed by restriction cleavage inhibition. Mutat Res 1996, 363(1):27-42.
72. Brash DE, Rudolph JA, Simon JA, Lin A, McKenna GJ, Baden HP, Halperin AJ, Ponten J: A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma. Proc Natl Acad Sci U S A 1991, 88(22):10124-10128.
73. Hollstein M, Sidransky D, Vogelstein B, Harris CC: p53 mutations in human cancers. Science 1991, 253(5015):49-53.
74. Harris CC, Hollstein M: Clinical implications of the p53 tumor-suppressor gene. N Engl J Med 1993, 329(18):1318-1327.
75. Ames BN, Shigenaga MK, Gold LS: DNA lesions, inducible DNA repair, and cell division: three key factors in mutagenesis and carcinogenesis. Environ Health Perspect 1993, 101 Suppl 5:35-44.
76. Poulsen HE, Prieme H, Loft S: Role of oxidative DNA damage in cancer initiation and promotion. Eur J Cancer Pre 1998, 7(1):9-16.
77. Szatrowski TP, Nathan CF: Production of Large Amounts of Hydrogen Peroxide by Human Tumor Cells. Cancer Research 1991, 51(3):794-798.
78. Paul T S: Reactive oxygen species in cancer cells: Live by the sword, die by the sword. Cancer Cell 2006, 10(3):175-176.
79. Trachootham D, Zhou Y, Zhang H, Demizu Y, Chen Z, Pelicano H, Chiao PJ, Achanta G, Arlinghaus RB, Liu J et al: Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by β-phenylethyl isothiocyanate. Cancer Cell 2006, 10(3):241-252.
80. Tayal D, Goswami B, Tyagi S, Chaudhary M, Mallika V: Interaction between dyslipidaemia, oxidative stress and inflammatory response in patients with angiographically proven coronary artery disease. Cardiovasc J Afr 2012, 23(1):23-27.
81. Rajesh KG, Surekha RH, Mrudula SK, Prasad Y, Sanjib KS, Prathiba N: Oxidative and nitrosative stress in association with DNA damage in coronary heart disease. Singapore Med J 2011, 52(4):283-288.
82. Verma S, Anderson TJ: Fundamentals of endothelial function for the clinical cardiologist. Circulation 2002, 105(5):546-549.
83. Shimokawa H: Primary endothelial dysfunction: atherosclerosis. J Mol Cell Cardiol 1999, 31(1):23-37.
84. Vallance P, Collier J, Moncada S: Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet 1989, 2(8670):997-1000.
85. Vanhoutte PM: Endothelium and control of vascular function. State of the Art lecture. Hypertension 1989, 13(6 Pt 2):658-667.
86. Panza JA, Quyyumi AA, Brush JE, Jr., Epstein SE: Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med 1990, 323(1):22-27.
87. Popolo A, Autore G, Pinto A, Marzocco S: Oxidative stress in cardiovascular disease and chronic renal failure. Free Radic Res 2013, 25:25.
88. Harman D: Aging: a theory based on free radical and radiation chemistry. J Gerontol 1956, 11(3):298-300.
89. Tzatsos A, Tsichlis PN: Energy Depletion Inhibits Phosphatidylinositol 3-Kinase/Akt Signaling and Induces Apoptosis via AMP-activated Protein Kinase-dependent Phosphorylation of IRS-1 at Ser-794. J Biol Chem 2007, 282(25):18069-18082.
90. Bitar MS, Al-Mulla F: ROS constitute a convergence nexus in the development of IGF1 resistance and impaired wound healing in a rat model of type 2 diabetes. Dis Model Mech 2012, 5(3):375-388.
91. Wellen KE, Hotamisligil GS: Inflammation, stress, and diabetes. J Clin Invest 2005, 115(5):1111-1119.
92. Boura-Halfon S, Zick Y: Serine kinases of insulin receptor substrate proteins. Vitam Horm 2009, 80:313-349.
93. Potashnik R, Bloch-Damti A, Bashan N, Rudich A: IRS1 degradation and increased serine phosphorylation cannot predict the degree of metabolic insulin resistance induced by oxidative stress. Diabetologia 2003, 46(5):639-648.
94. Higashi Y, Pandey A, Goodwin B, Delafontaine P: Insulin-like growth factor-1 regulates glutathione peroxidase expression and activity in vascular endothelial cells: Implications for atheroprotective actions of insulin-like growth factor-1. Biochim Biophys Acta-Mol Basis Dis 2013, 1832(3):391-399.
95. Shai SY, Sukhanov S, Higashi Y, Vaughn C, Kelly J, Delafontaine P: Smooth muscle cell-specific insulin-like growth factor-1 overexpression in Apoe-/- mice does not alter atherosclerotic plaque burden but increases features of plaque stability. Arterioscler Thromb Vasc Biol 2010, 30(10):1916-1924.
96. Kroemer G, El-Deiry WS, Golstein P, Peter ME, Vaux D, Vandenabeele P, Zhivotovsky B, Blagosklonny MV, Malorni W, Knight RA et al: Classification of cell death: recommendations of the Nomenclature Committee on Cell Death. Cell Death Differ 2005, 12(S2):1463-1467.
97. Ryter SW, Kim HP, Hoetzel A, Park JW, Nakahira K, Wang X, AM C: Mechanisms of cell death in oxidative stress. Antioxid Redox Signal. Antioxid Redox Signal 2007, 9:49-89.
98. Baines CP, Kaiser RA, Purcell NH, Blair NS, Osinska H, Hambleton MA, Brunskill EW, Sayen MR, Gottlieb RA, Dorn GW et al: Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 2005, 434(7033):658-662.
99. Nakagawa T, Shimizu S, Watanabe T, Yamaguchi O, Otsu K, Yamagata H, Inohara H, Kubo T, Tsujimoto Y: Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 2005, 434(7033):652-658.
100. Kyungsun C, Jinho K, Kim GW, Chulhee C: Oxidative Stress-Induced Necrotic Cell Death via Mitochondira-Dependent Burst of Reactive Oxygen Species. Curr Neurovasc Res 2009, 6(4):213-222.
101. Chen Y, Azad MB, Gibson SB: Superoxide is the major reactive oxygen species regulating autophagy. Cell Death Differ 2009, 16(7):1040-1052.
102. Huang J, Canadien V, Lam GY, Steinberg BE, Dinauer MC, Magalhaes MAO, Glogauer M, Grinstein S, Brumell JH: Activation of antibacterial autophagy by NADPH oxidases. Proc Natl Acad Scin U S A 2009, 106(15):6226-6231.
103. Scherz-Shouval R, Shvets E, Fass E, Shorer H, Gil L, Elazar Z: Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J 2007, 26(7):1749-1760.
104. Lee JS, Giordano S, Zhang JH: Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling. Biochem J 2012, 441:523-540.
105. Chen Y, McMillan-Ward E, Kong J, Israels SJ, Gibson SB: Oxidative stress induces autophagic cell death independent of apoptosis in transformed and cancer cells. Cell Death Differ 2007, 15(1):171-182.
106. Gustafsson AB, Gottlieb RA: Recycle or die: the role of autophagy in cardioprotection. J Mol Cell Cardiol 2008, 44(4):654-661.
107. Sridharan S, Jain K, Basu A: Regulation of Autophagy by Kinases. Cancers 2011, 3(2):2630-2654.
108. Codogno P, Meijer AJ: Autophagy and signaling: their role in cell survival and cell death. Cell Death Differ 2005, 12(S2):1509-1518.
109. Levine B, Yuan J: Autophagy in cell death: an innocent convict? J Clin Invest 2005, 115(10):2679-2688.
110. Elgendy M, Sheridan C, Brumatti G, Martin Seamus J: Oncogenic Ras-Induced Expression of Noxa and Beclin-1 Promotes Autophagic Cell Death and Limits Clonogenic Survival. Mol Cell 2011, 42(1):23-35.
111. Voss V, Senft C, Lang V, Ronellenfitsch MW, Steinbach JP, Seifert V, Kögel D: The Pan-Bcl-2 Inhibitor (−)-Gossypol Triggers Autophagic Cell Death in Malignant Glioma. Mol Cancer Res 2010, 8(7):1002-1016.
112. Puissant A, Robert G, Fenouille N, Luciano F, Cassuto J-P, Raynaud S, Auberger P: Resveratrol Promotes Autophagic Cell Death in Chronic Myelogenous Leukemia Cells via JNK-Mediated p62/SQSTM1 Expression and AMPK Activation. Cancer Res 2010, 70(3):1042-1052.
113. Negri T, Tarantino E, Orsenigo M, Reid JF, Gariboldi M, Zambetti M, Pierotti MA, Pilotti S: Chromosome band 17q21 in breast cancer: significant association between beclin 1 loss and HER2/NEU amplification. Genes Chromosomes Cancer 2010, 49(10):901-909.
114. Yue Z, Jin S, Yang C, Levine AJ, Heintz N: Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci U S A 2003, 100(25):15077-15082.
115. Mathew R, Karp CM, Beaudoin B, Vuong N, Chen G, Chen HY, Bray K, Reddy A, Bhanot G, Gelinas C et al: Autophagy suppresses tumorigenesis through elimination of p62. Cell 2009, 137(6):1062-1075.
116. Maiuri MC, Tasdemir E, Criollo A, Morselli E, Vicencio JM, Carnuccio R, Kroemer G: Control of autophagy by oncogenes and tumor suppressor genes. Cell Death Differ 2009, 16(1):87-93.
117. Morselli E, Galluzzi L, Kepp O, Vicencio JM, Criollo A, Maiuri MC, Kroemer G: Anti- and pro-tumor functions of autophagy. Biochim Biophys Acta 2009, 9(32):21.
118. Schoenlein PV, Periyasamy-Thandavan S, Samaddar JS, Jackson WH, Barrett JT: Autophagy facilitates the progression of ERalpha-positive breast cancer cells to antiestrogen resistance. Autophagy 2009, 5(3):400-403.
119. Yang PM, Liu YL, Lin YC, Shun CT, Wu MS, Chen CC: Inhibition of autophagy enhances anticancer effects of atorvastatin in digestive malignancies. Cancer Res 2010, 70(19):7699-7709.
120. Guo XL, Li D, Sun K, Wang J, Liu Y, Song JR, Zhao QD, Zhang SS, Deng WJ, Zhao X et al: Inhibition of autophagy enhances anticancer effects of bevacizumab in hepatocarcinoma. J Mol Med (Berl) 2012.
121. Amaravadi RK, Yu D, Lum JJ, Bui T, Christophorou MA, Evan GI, Thomas-Tikhonenko A, Thompson CB: Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Invest 2007, 117(2):326-336.
122. De Meyer GRY, Martinet W: Autophagy in the cardiovascular system. Biochim Biophys Acta 2009, 1793(9):1485-1495.
123. Libby P: Inflammation in atherosclerosis. Nature 2002, 20(6917):868-874.
124. Martinet W, De Meyer GR: Autophagy in atherosclerosis. Curr Atheroscler Rep 2008, 10(3):216-223.
125. Arora M, Kaul D: Coronary atherosclerosis: Significance of autophagic armour. World J Cardiol 2012, 4(9):271-274.
126. Martinet W, De Bie M, Schrijvers DM, De Meyer GR, Herman AG, Kockx MM: 7-ketocholesterol induces protein ubiquitination, myelin figure formation, and light chain 3 processing in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 2004, 24(12):2296-2301.
127. Jia G, Cheng G, Gangahar DM, Agrawal DK: Insulin-like growth factor-1 and TNF-alpha regulate autophagy through c-jun N-terminal kinase and Akt pathways in human atherosclerotic vascular smooth cells. Immunol Cell Biol 2006, 84(5):448-454.
128. Liao X, Sluimer JC, Wang Y, Subramanian M, Brown K, Pattison JS, Robbins J, Martinez J, Tabas I: Macrophage autophagy plays a protective role in advanced atherosclerosis. Cell Metab 2012, 15(4):545-553.
129. Razani B, Feng C, Coleman T, Emanuel R, Wen H, Hwang S, Ting Jenny P, Virgin Herbert W, Kastan Michael B, Semenkovich Clay F: Autophagy Links Inflammasomes to Atherosclerotic Progression. Cell Metab 2012, 15(4):534-544.
130. Fischman DL, Leon MB, Baim DS, Schatz RA, Savage MP, Penn I, Detre K, Veltri L, Ricci D, Nobuyoshi M et al: A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis Study Investigators. N Engl J Med 1994, 331(8):496-501.
131. Serruys PW, de Jaegere P, Kiemeneij F, Macaya C, Rutsch W, Heyndrickx G, Emanuelsson H, Marco J, Legrand V, Materne P et al: A Comparison of Balloon-Expandable-Stent Implantation with Balloon Angioplasty in Patients with Coronary Artery Disease. N Engl J Med 1994, 331(8):489-495.
132. Hoffmann R, Mintz GS, Dussaillant GR, Popma JJ, Pichard AD, Satler LF, Kent KM, Griffin J, Leon MB: Patterns and mechanisms of in-stent restenosis. A serial intravascular ultrasound study. Circulation 1996, 94(6):1247-1254.
133. Scott NA: Restenosis following implantation of bare metal coronary stents: pathophysiology and pathways involved in the vascular response to injury. Adv Drug Deliv Rev 2006, 58(3):358-376.
134. Clowes AW, Reidy MA, Clowes MM: Mechanisms of stenosis after arterial injury. Lab Invest 1983, 49(2):208-215.
135. Clowes AW, Reidy MA, Clowes MM: Kinetics of cellular proliferation after arterial injury. I. Smooth muscle growth in the absence of endothelium. Lab Invest 1983, 49(3):327-333.
136. Zohlnhofer D, Nuhrenberg TG, Neumann FJ, Richter T, May AE, Schmidt R, Denker K, Clauss MA, Schomig A, Baeuerle PA: Rapamycin effects transcriptional programs in smooth muscle cells controlling proliferative and inflammatory properties. Mol Pharmacol 2004, 65(4):880-889.
137. Marx SO, Jayaraman T, Go LO, Marks AR: Rapamycin-FKBP inhibits cell cycle regulators of proliferation in vascular smooth muscle cells. Circ Res 1995, 76(3):412-417.
138. Babapulle MN, Joseph L, Belisle P, Brophy JM, Eisenberg MJ: A hierarchical Bayesian meta-analysis of randomised clinical trials of drug-eluting stents. Lancet 2004, 364(9434):583-591.
139. Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, O'Shaughnessy C, Caputo RP, Kereiakes DJ, Williams DO, Teirstein PS et al: Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003, 349(14):1315-1323.
140. Nair S, Ren J: Autophagy and cardiovascular aging: lesson learned from rapamycin. Cell cycle 2012, 11(11):2092-2099
141. Huang J, Lam GY, Brumell JH: Autophagy signaling through reactive oxygen species. Antioxid Redox Signal 2011, 14(11):2215-2231.
142. Scherz-Shouval R, Elazar Z: Regulation of autophagy by ROS: physiology and pathology. Trends Biochem Sci 2011, 36(1):30-38.
143. Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH, Wesley JB, Gonzalez FJ, Semenza GL: Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem 2008, 283(16):10892-10903.
144. Jung S-N, Yang WK, Kim J, Kim HS, Kim EJ, Yun H, Park H, Kim SS, Choe W, Kang I et al: Reactive oxygen species stabilize hypoxia-inducible factor-1 alpha protein and stimulate transcriptional activity via AMP-activated protein kinase in DU145 human prostate cancer cells. Carcinogenesis 2008, 29(4):713-721.
145. Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, Turk BE, Shaw RJ: AMPK Phosphorylation of Raptor Mediates a Metabolic Checkpoint. Mol Cell 2008, 30(2):214-226.
146. Yang Z, Klionsky DJ: Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol 2010, 22(2):124-131.
147. Inoki K, Zhu T, Guan K-L: TSC2 Mediates Cellular Energy Response to Control Cell Growth and Survival. Cell 2003, 115(5):577-590.
148. Alexander A, Cai S-L, Kim J, Nanez A, Sahin M, MacLean KH, Inoki K, Guan K-L, Shen J, Person MD et al: ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS. Proc Natl Acad Sci
U S A 2010, 107(9):4153-4158.
149. Horman S, Vertommen D, Heath R, Neumann D, Mouton V, Woods A, Schlattner U, Wallimann T, Carling D, Hue L et al: Insulin Antagonizes Ischemia-induced Thr172 Phosphorylation of AMP-activated Protein Kinase α-Subunits in Heart via Hierarchical Phosphorylation of Ser485/491. J Biol Chem 2006, 281(9):5335-5340.
150. Scherz-Shouval R, Elazar Z: ROS, mitochondria and the regulation of autophagy. Trends Cell Biol 2007, 17(9):422-427.
151. Yu L, Wan F, Dutta S, Welsh S, Liu Z, Freundt E, Baehrecke EH, Lenardo M: Autophagic programmed cell death by selective catalase degradation. Proc Natl Acad Sci U S A 2006, 103(13):4952-4957.
152. Almind K, Frederiksen SK, Bernal D, Hansen T, Ambye L, Urhammer S, Ekstrom CT, Berglund L, Reneland R, Lithell H et al: Search for variants of the gene-promoter and the potential phosphotyrosine encoding sequence of the insulin receptor substrate-2 gene: evaluation of their relation with alterations in insulin secretion and insulin sensitivity. Diabetologia 1999, 42(10):1244-1249.
153. Mammarella S, Romano F, Di Valerio A, Creati B, Esposito DL, Palmirotta R, Capani F, Vitullo P, Volpe G, Battista P et al: Interaction between the G1057D variant of IRS-2 and overweight in the pathogenesis of type 2 diabetes. Hum Mol Genet 2000, 9(17):2517-2521.
154. Robins SJ, Lyass A, Zachariah JP, Massaro JM, Vasan RS: Insulin resistance and the relationship of a dyslipidemia to coronary heart disease: the Framingham Heart Study. Arterioscler Thromb Vasc Biol 2011, 31(5):1208-1214.
155. Reaven GM: Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988, 37(12):1595-1607.
156. DeFronzo RA, Ferrannini E: Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991, 14(3):173-194.
157. Marenberg ME, Risch N, Berkman LF, Floderus B, de Faire U: Genetic susceptibility to death from coronary heart disease in a study of twins. N Engl J Med 1994, 330(15):1041-1046.
158. Kannel WB, McGee DL: Diabetes and cardiovascular disease. The Framingham study. JAMA 1979, 241(19):2035-2038.
159. Korenman SG, Kahn CR: Atlas of Clinical Endocrinology, Diabetes, vol. 2: John Willey & Sons; 1999.
160. Kahn CR: Insulin action, diabetogenes, and the cause of type II diabetes. Diabetes 1994, 43:1066-1084.
161. Almind K, Inoue G, Pedersen O, Kahn CR: A common amino acid polymorphism in insulin receptor substrate-1 causes impaired insulin signaling. Evidence from transfection studies. J Clin Invest 1996, 97(11):2569-2575.
162. Clausen JO, Hansen T, Bjorbaek C, Echwald SM, Urhammer SA, Rasmussen S, Andersen CB, Hansen L, Almind K, Pedersen O et al: Insulin resistance: interactions between obesity and a common variant of insulin receptor substrate-1. Lancet 1995, 346(8972):397-402.
163. Burguete-Garcia AI, Cruz-Lopez M, Madrid-Marina V, Lopez-Ridaura R, Hernández-Avila M, Cortina B, Gómez RE, Velasco-Mondragón E: Association of Gly972Arg polymorphism of IRS1 gene with type 2 diabetes mellitus in lean participants of a national health survey in Mexico: a candidate gene study. Metab Clin Exp 2010, 59(1):38-45.
164. Kong LF, Zhao YY, Li Q, Zheng XM, Ding Q, Liu H, GL L: Study on the relationship between G1057D variants of IRS2 gene and obese T2DM in Chinese Han subjects. Chin J Medical Genetics 2005, 22(4):387-390.
165. Wang H, Rissanen J, Miettinen R, Kärkkäinen P, Kekäläinen P, Kuusisto J, Mykkänen L, Karhapää P, Laakso M: New Amino Acid Substitutions in the IRS-2 Gene in Finnish and Chinese Subjects With Late-Onset Type 2 Diabetes. Diabetes 2001, 50(8):1949-1951.
166. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, Jr., Jones DW, Materson BJ, Oparil S, Wright JT, Jr. et al: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003, 289(19):2560-2572.
167. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001, 285(19):2486-2497.
168. 2006 WHODadodmaihRoaWcGWHO.
169. Matthews D, Hosker J, Rudenski A, Naylor B, Treacher D, Turner R: Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985, 28(7):412-419.
170. Shephard DA: The 1975 Declaration of Helsinki and consent Can Med Assoc J 1976, 115(12):1191-1192.
171. Li Y-H, Chen J-H, Wu H-L, Shi G-Y, Huang H-C, Chao T-H, Tsai W-C, Tsai L-M, Guo H-R, Wu W-S et al: G-33A mutation in the promoter region of thrombomodulin gene and its association with coronary artery disease and plasma soluble thrombomodulin levels. Am J Cardiol 2000, 85(1):8-12.
172. Dawson B, Trapp RG: Basic and Clinical Biostatistics 4th edn: Lange Medical Books/McGraw-Hill; 2004.
173. Kannel W, McGee D: Diabetes and cardiovascular risk factors: the Framingham study. Circulation 1979, 59(1):8-13.
174. Halvatsiotis I, Tsiotra PC, Ikonomidis I, Kollias A, Mitrou P, Maratou E, Boutati E, Lekakis J, Dimitriadis G, Economopoulos T et al: Genetic variation in the adiponectin receptor 2 (ADIPOR2) gene is associated with coronary artery disease and increased ADIPOR2 expression in peripheral monocytes. Cardiovasc Diabetol 2010, 9:10.
175. Siitonen N, Pulkkinen L, Lindstrom J, Kolehmainen M, Schwab U, Eriksson JG, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Tuomilehto J, Uusitupa M: Association of ADIPOR2 gene variants with cardiovascular disease and type 2 diabetes risk in individuals with impaired glucose tolerance: the Finnish Diabetes Prevention Study. Cardiovasc Diabetol 2011, 10:83.
176. Chaudhary R, Likidlilid A, Peerapatdit T, Tresukosol D, Srisuma S, Ratanamaneechat S, Sriratanasathavorn C: Apolipoprotein E gene polymorphism: effects on plasma lipids and risk of type 2 diabetes and coronary artery disease. Cardiovasc Diabetol 2012, 11:36.
177. Shah S, Casas JP, Gaunt TR, Cooper J, Drenos F, Zabaneh D, Swerdlow DI, Shah T, Sofat R, Palmen J et al: Influence of common genetic variation on blood lipid levels, cardiovascular risk, and coronary events in two British prospective cohort studies. Eur Heart J 2012, 13:13.
178. Muendlein A, Saely CH, Geller-Rhomberg S, Sonderegger G, Rein P, Winder T, Beer S, Vonbank A, Drexel H: Single Nucleotide Polymorphisms of TCF7L2 Are Linked to Diabetic Coronary Atherosclerosis. PLoS ONE 2011, 6(3):e17978.
179. Opstad TB, Pettersen AA, Arnesen H, Seljeflot I: Circulating levels of IL-18 are significantly influenced by the IL-18 +183 A/G polymorphism in coronary artery disease patients with diabetes type 2 and the metabolic syndrome: an observational study. Cardiovasc Diabetol 2011, 10:110.
180. Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB: Prediction of coronary heart disease using risk factor categories. Circulation 1998, 97(18):1837-1847.
181. Assmann G, Cullen P, Schulte H: Simple scoring scheme for calculating the risk of acute coronary events based on the 10-year follow-up of the prospective cardiovascular Munster (PROCAM) study. Circulation 2002, 105(3):310-315.
182. Salazar JJ, Van Houten B: Preferential mitochondrial DNA injury caused by glucose oxidase as a steady generator of hydrogen peroxide in human fibroblasts. Mutat Res 1997, 385(2):139-149.
183. Huser CA, Pringle MA, Heath VJ, Bell AK, Kendrick H, Smalley MJ, Crighton D, Ryan KM, Gusterson BA, Stein T: TSC-22D1 isoforms have opposing roles in mammary epithelial cell survival. Cell Death Differ 2010, 17(2):304-315.
184. Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, Kominami E, Ohsumi Y, Yoshimori T: LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J 2000, 19(21):5720-5728.
185. Mizushima N, Yoshimori T: How to Interpret LC3 Immunoblotting. Autophagy 2007, 3(6):542-545.
186. Mizushima N, Yoshimori T, Levine B: Methods in Mammalian Autophagy Research. Cell 2010, 140(3):313-326.
187. Levine B, Klionsky DJ: Development by Self-Digestion: Molecular Mechanisms and Biological Functions of Autophagy. Dev Cell 2004, 6(4):463-477.
188. Ichimura Y, Kirisako T, Takao T, Satomi Y, Shimonishi Y, Ishihara N, Mizushima N, Tanida I, Kominami E, Ohsumi M et al: A ubiquitin-like system mediates protein lipidation. Nature 2000, 408(6811):488-492.
189. Rubinsztein DC, Gestwicki JE, Murphy LO, Klionsky DJ: Potential therapeutic applications of autophagy. Nat Rev Drug Discov 2007, 6(4):304-312.
190. Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Scaravilli F, Easton DF, Duden R, O'Kane CJ et al: Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 2004, 36(6):585-595.
191. Kroemer G, Levine B: Autophagic cell death: the story of a misnomer. Nat Rev Mol Cell Biol 2008, 9(12):1004-1010.
192. Chen Y, Azad MB, Gibson SB: Methods for detecting autophagy and determining autophagy-induced cell death. Can J Physiol Pharmacol 2010, 88(3):285-295.
193. Hietakangas V, Cohen SM: Regulation of tissue growth through nutrient sensing. Annu Rev Genet 2009, 43:389-410 LID - 310.1146/annurev-genet-102108-134815 [doi].
194. Osborne JK, Zaganjor E, Cobb MH: Signal control through Raf: in sickness and in health. Cell Res 2012, 22(1):14-22.
195. Shen S, Kepp O, Kroemer G: The end of autophagic cell death? Autophagy 2012, 8(1):1-3.
196. Boya P, González-Polo R-A, Casares N, Perfettini J-L, Dessen P, Larochette N, Métivier D, Meley D, Souquere S, Yoshimori T et al: Inhibition of Macroautophagy Triggers Apoptosis. MolCell Biol 2005, 25(3):1025-1040.
197. Lum JJ, Bauer DE, Kong M, Harris MH, Li C, Lindsten T, Thompson CB: Growth Factor Regulation of Autophagy and Cell Survival in the Absence of Apoptosis. Cell 2005, 120(2):237-248.
198. Shen S, Kepp O, Michaud M, Martins I, Minoux H, Metivier D, Maiuri MC, Kroemer RT, Kroemer G: Association and dissociation of autophagy, apoptosis and necrosis by systematic chemical study. Oncogene 2011, 30(45):4544-4556.
199. Riehle C, Bugger H, Sena S, Pires KM, Theobald HA, Perry-Garza CN, Frank D, Dong X, Moon A, Gottlieb R et al: Insulin Receptor Substrates (IRS) are Critical Regulators of Autophagy and Cardiomyocyte Survival [abstract]. Circulation 2009, 120:S901.
200. Cagnol S, Chambard J-C: ERK and cell death: Mechanisms of ERK-induced cell death – apoptosis, autophagy and senescence. FEBS J 2010, 277(1):2-21.
201. Scott RC, Schuldiner O, Neufeld TP: Role and Regulation of Starvation-Induced Autophagy in the Drosophila Fat Body. Dev Cell 2004, 7(2):167-178.
202. Zeng X, Kinsella TJ: Mammalian Target of Rapamycin and S6 Kinase 1 Positively Regulate 6-thioguanine-Induced Autophagy. Cancer Res 2008, 68(7):2384-2390.
203. Khalili K, Del Valle L, Wang JY, Darbinian N, Lassak A, Safak M, Reiss K: T-antigen of human polyomavirus JC cooperates withIGF-IR signaling system in cerebellar tumors of the childhood-medulloblastomas. Anticancer Res 2003, 23(3A):2035-2041.
204. Fei ZL, D'Ambrosio C, Li S, Surmacz E, Baserga R: Association of insulin receptor substrate 1 with simian virus 40 large T antigen. MolCell Biol 1995, 15(8):4232-4239.
205. Li L, Qi X, Williams M, Shi Y, Keegan AD: Overexpression of Insulin Receptor Substrate-1, But Not Insulin Receptor Substrate-2, Protects a T Cell Hybridoma from Activation-Induced Cell Death. J Immunol 2002, 168(12):6215-6223.
206. Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, Tanaka K, Cuervo AM, Czaja MJ: Autophagy regulates lipid metabolism. Nature 2009, 458(7242):1131-1135.
207. Singh R, Xiang Y, Wang Y, Baikati K, Cuervo AM, Luu YK, Tang Y, Pessin JE, Schwartz GJ, Czaja MJ: Autophagy regulates adipose mass and differentiation in mice. J Clin Invest 2009, 119(11):3329-3339
208. Sanchez-Gurmaches J, Cruz-Garcia L, Gutierrez J, Navarro I: mRNA expression of fatty acid transporters in rainbow trout: in vivo and in vitro regulation by insulin, fasting and inflammation and infection mediators. Comp Biochem Physiol A Mol Integr Physiol 2012, 163(2):177-188.
209. Kaminskyy VO, Piskunova T, Zborovskaya IB, Tchevkina EM, Zhivotovsky B: Suppression of basal autophagy reduces lung cancer cell proliferation and enhances caspase-dependent and -independent apoptosis by stimulating ROS formation. Autophagy 2012, 8:7.
210. Indolfi C, Avvedimento EV, Rapacciuolo A, Esposito G, Di Lorenzo E, Leccia A, Pisani A, Chieffo A, Coppola A, Chiariello M: In vivo gene transfer: prevention of neointima formation by inhibition of mitogen-activated protein kinase kinase. Basic Res Cardiol 1997, 92(6):378-384.
211. Huang J, Kontos CD: Inhibition of vascular smooth muscle cell proliferation, migration, and survival by the tumor suppressor protein PTEN. Arterioscler Thromb Vasc Biol 2002, 22(5):745-751.
212. Veldhoen RA, Banman SL, Hemmerling DR, Odsen R, Simmen T, Simmonds AJ, Underhill DA, Goping IS: The chemotherapeutic agent paclitaxel inhibits autophagy through two distinct mechanisms that regulate apoptosis. Oncogene 2013, 32(6):736-746.
213. Finn AV, Nakazawa G, Joner M, Kolodgie FD, Mont EK, Gold HK, Virmani R: Vascular responses to drug eluting stents: importance of delayed healing. Arterioscler Thromb Vasc Biol 2007, 27(7):1500-1510.
214. Hayashi S, Yamamoto A, You F, Yamashita K, Ikegame Y, Tawada M, Yoshimori T, Shimizu S, Nakashima S: The stent-eluting drugs sirolimus and paclitaxel suppress healing of the endothelium by induction of autophagy. Am J Pathol 2009, 175(5):2226-2234.
215. Yuan Y, Li P, Ye J: Lipid homeostasis and the formation of macrophage-derived foam cells in atherosclerosis. Protein Cell 2012, 3(3):173-181.
216. Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, Tanaka K, Cuervo AM, Czaja MJ: Autophagy regulates lipid metabolism. Nature 2009, 458(7242):1131-1135.
論文全文使用權限
  • 同意授權校內瀏覽/列印電子全文服務,於2023-01-01起公開。
  • 同意授權校外瀏覽/列印電子全文服務,於2013-05-31起公開。


  • 如您有疑問,請聯絡圖書館
    聯絡電話:(06)2757575#65773
    聯絡E-mail:etds@email.ncku.edu.tw