摘要
合成的生长激素释放肽具有很强的促生长激素释放作用,还有许多其它生物活性。最近研究发现,肽类的GHS有明显的心血管作用。本实验选用合成的生长激素释放肽之一hexarelin,通过离体和在体实验,从整体、细胞、分子水平研究了hexarelin对心力衰竭过程心肌细胞凋亡、心肌细胞肥大、以及对动脉粥样硬化的影响。首先,在第一、二部分实验,我们以离体和在体实验,研究了hexarelin对Ang Ⅱ诱导的原代培养新生乳鼠心肌细胞凋亡的作用和四种GHRP对心衰大鼠心肌细胞凋亡的影响。结果表明,hexarelin可明显抑制Ang Ⅱ诱导的心肌细胞凋亡,而且四种GHRP对压力负荷型心衰大鼠的心功能有明显改善作用,对心衰时心肌细胞的凋亡有明显抑制作用。其作用机制可能与抑制caspase-3酶活性,抑制bax mRNA的表达,增加bcl-2 mRNA表达,抑制p38MAPK蛋白表达有关。鉴于GHRP对心衰大鼠有明显治疗作用,而心肌细胞肥大是心力衰竭的重要发病过程之一,在第三部分我们观察了hexarelin对Ang Ⅱ诱发的心肌细胞肥大的作用以及hexarelin对SHR心肌肥厚的作用。结果提示hexarelin有明显抗Ang Ⅱ诱发的心肌细胞肥大和抑制SHR心肌肥厚的作用。其作用机制与抑制AT1受体mRNA表达和上调AT2受体mRNA的表达,抑制ERK1/2的活性有关。从前三部分实验结果可见,hexarelin对心血管系统中的肾素-血管紧张素系统有明显影响,提示hexarelin对动脉粥样硬化的发生发展可能也有重要作用。因此在第四部分,我们观察了hexarelin对动脉粥样硬化大鼠的影响和对AngⅡ诱发的血管平滑肌细胞增殖的作用。结果显示,hexarelin有明显的抗动脉粥样硬化作用,其机制可能与增加血清HDL-c,NO,减少LDL-c,减少主动脉中脂质和钙的沉积,抑制Ang Ⅱ诱发的血管平滑肌细胞增殖密切相关,还可能与CD36 mRNA的表达上调有关。在离体和在体状态下,给予GHRP或hexarelin,都可以明显上调GHS-R mRNA的表达,提示hexarelin的心血管保护作用还可能与GHS-R mRNA的表达增加有关。
Synthetic growth hormone releasing peptides possess strong growth hormone-releasing effects and effusive peripheral activities. Recently, several independent observations indicated that GHRP exerts cardiovascular activities. We investigated the effects of hexarelin on cardiomyocyte apoptosis in rats with heart failure, cardiac hypertrophy and atherosclerosis in in vivo and in vitro models. At first, the effects of hexarelin on cardiomyocyte apoptosis induced by Ang II, and effects of four GHRPs (GHRP-1, GHRP-2, GHRP-6, hexarelin) on cardiomyocyte apoptosis in pressure-over load heart failure rat model were observed in part I and part II. The results showed that (1) hexarelin inhibited cardiomyocyte apoptosis induced by AngII; (2) GHRPs improved cardiac dysfunction and inhibit the cardiomyocyte apoptosis in rats with heart failure. These results indicated that hexarelin abates cardiomyocytes from Ang II-and heart failure-induced cardiomyocyte apoptosis in rat. The possible mechanisms were possibly via inhibiting the activity of caspase-3, inhibiting bax mRNA expression, increasing the expression of bcl-2 mRNA and inhibiting the expression of p38MAPK protein. (3) Hexarelin inhibited cardiomyocyte hypertrophy induced by Ang II and inhibit the cardiac hypertrophy of SHR. The mechanisms of the antihypertrophy effect of hexarelin may be associated with inhibition of ATI receptor mRNA expression, with upregulation of the expression of AT2 receptor mRNA and ERK1/2 activity. As hexarelin could affect the renin-angiotensin system, with the inhibition of hexarelin may have effect on the development of atherosclerosis. We investigated the effect of hexarelin on the astherosclerosis model of rat and the effect of hexarelin on proliferation of vascular smooth muscle cell(VSMC) induced by Ang II. (4) Hexarelin showed obvious antiatheosclerosis effects. The underlying mechanisms may related with the increasing of serum HDL-c and NO, the decreasing of serum LDL-c, the attenuate of accumulation of lipid and calcium deposits in aorta and the inhibition of VSMC proliferation induced by Ang II. These effects of GHRP may be also associated with the upregulation of CD36 mRNA. Taken together, administration of
引文
1. Anversa P, Kajstura J, Olivetti G. Myocyte death in heart failure. Curr Opin Cardiol. 1996; 11:245-251
2. Colucci WS. Apoptosis in the heart. N Engl J Med. 1996; 335: 1224-1226
3. MacLellan WR, Schneider MD. Death by design. Programmed cell death in cardiovascular biology and disease. Circ Res. 1997; 81: 137-144
4. Narula J, Haider N, Virmani R, et al. Apoptosis in myocytes in end-stage heart failure. N Engl J Med. 1996; 335: 1182-1189
5. Olivetti G, Abbi R, Quaini F, et al. Apoptosis in the failing human heart. N Engl J Med. 1997; 336: 1131-1141
6. Olivetti G, Quaini F, Sala R, et al. Acute myocardial infarction in humans is associated with activation of programmed myocyte cell death in the surviving portion of the heart. J Mol Cell Cardiol. 1996; 28: 2005-2016
7. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med. 1992; 327: 685-691
8. Li Z, Bing OH, Long X, et al. Increased cardiomyocyte apoptosis during the transition to heart failure in the spontaneously hypertensive rat. Am J Physiol. 1997; 272:H2313-H2319
9. Cheng W, Kajstura J, Nitahara JA, et al. Programmed myocyte cell death affects the viable myocardium after infarction in rats. Exp Cell Res. 1996; 226: 316-327
10. Sharov VG, Sabbah HN, Shimoyama H, et al. Evidence of cardiocyte apoptosis in myocardium of dogs with chronic heart failure. Am J Pathol. 1996; 148: 141-14911. Wollert KC, Drexler H. The renin-angiotensin system and experimental heart failure. Cardiovasc Res. 1999; 43:838-849
12. Kajstura J, Cigola E, Malhotra A, et al. Angiotensin II induces apoptosis of adult ventricular myocytes in vitro. J Mol Cell Cardiol. 1997; 29: 859-870,
13. Hasegawa K, Iwai-Kanai E, Sasayama S. Neurohormonal regulation of myocardial cell apoptosis during the development of heart failure. J Cell Physiol. 2001, 186: 11-18
14. Teiger E, Than VD, Richard L, et al. Apoptosis in pressure overload-induced heart hypertrophy in the rat. J Clin Invest. 1996; 97: 2891-2897
15. Weinberg EO, Schoen FJ, George D, et al. Angiotensin-converting enzyme inhibition prolongs survival and modifies the transition to heart failure in rats with pressure overload hypertrophy due to ascending aortic stenosis. Circulation 1994; 90: 1410-1422
16. Casanueva FF, Dieguez C. Growth Hormone Secretagogues: Physiological Role and Clinical Utility. Trends Endocrinol Metab. 1999; 10: 30-38
17. Muccioli G, Broglio F, Valetto MR, et al. Growth hormone-releasing peptides and the cardiovascular system. Ann. Endocrinol. (Paris) 2000; 61: 27-31
18. Locatelli V, Rossoni G, Schweiger F, et al. Growth hormone-independent cardioprotective effects of hexarelin in the rat. Endocrinology. 1999; 140: 4024-4031
19. Bisi G, Podio V, Valetto MR, et al. Acute cardiovascular and hormonal effects of GH and hexarelin, a synthetic GH-releasing peptide, in humans. J Endocrinol Invest. 1999; 22: 266-272
20. Filigheddu N, Fubini A, Baldanzi G, et al. Hexarelin protects H9c2 cardiomyocytes from doxorubicin-induced cell death. Endocrine. 2001, 14: 113-119
21. Ekhterae D, Lin Z, Lundberg MS, et al. ARC inhibits cytochrome c release from mitochondria and protects against hypoxia-induced apoptosis in heart-derived H9c2 cells. Circ Res. 1999; 85: E70-E77
22. Wang L, Ma W, Markovich R, et al. Regulation of cardiomyocyte apoptotic signaling by insulin-like growth factor I. Circ Res. 1998; 83: 516-522
23. Wang L, Ma W, Markovich R, et al. Insulin-like growth factor I modulates induction of apoptotic signaling in H9C2 cardiac muscle cells. Endocrinology. 1998; 139: 1354-1360
24. Pettersson I, Muccioli G, Granata R, et al. Natural (ghrelin) and synthetic (hexarelin) GH secretagogues stimulate H9c2 cardiomyocyte cell proliferation. J Endocrinol. 2002; 175:201-209
25. Iwaki K, Sukhatme VP, Shubeita HE, et al. Alpha- and beta-adrenergic stimulation induces distinct patterns of immediate early gene expression in neonatal rat myocardial cells. fos/jun expression is associated with sarcomere assembly; Egr-1 induction is primarily an alpha 1-mediated response. J Biol Chem. 1990; 265: 13809-13817
26. Miki N, Hamamori Y, Hirata K, et al. Transforming growth factor-beta 1 potentiated alpha 1-adrenergic and stretch-induced c-fos mRNA expression in rat myocardial cells. Circ Res. 1994; 75: 8-14
27. Herrmann M, Lorenz HM, Voll R, et al. A rapid and simple method for the isolation of apoptotic DNA fragments. Nucleic Acids Res. 1994; 22: 5506-5507
28. Darzynkiewicz Z, Juan G, Li X, et al. Cytometry in cell necrobiology: analysis of apoptosis and accidental cell death (necrosis). Cytometry. 1997; 27: 1-20
29. Fraker PJ, King LE, Lill-Elghanian D, et al. Quantification of apoptotic events in pure and heterogeneous populations of cells using the flow cytometer. Methods CellBiol. 1995; 46: 57-76
30. Nagaya N, Kojima M, Uematsu M, et al. Hemodynamic and hormonal effects of human ghrelin in healthy volunteers. Am J Physiol Regul Integr Comp Physiol. 2001; 280: R1483-R1487
31. Datta SR, Dudek H, Tao X, et al. Akt phosphorylation of BAD couple survival signals to the cell- intrinsic death machinery. Cell. 1997; 91: 231-241
32. Sato T, Irie S, Krajewski S, et al. Cloning and sequencing of a cDNA encoding the rat Bcl-2 protein. Gene. 1994; 140: 291-292
33. Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 1993; 74: 609-619
34. Kumar S. The apoptotic cysteine protease CPP32. Int J Biochem Cell Biol. 1997; 29: 393-396
35. Vaux DL , A Strasser. The molecular biology of apoptosis. Proc Natl Acad Sci USA. 1996; 93:2239-2244
36. Cigola E, Kajstura J, Li B, et al. Angiotensin II activates programmed myocyte cell death in vitro. Exp Cell Res. 1997; 231: 363-371
37. Bodart V, Bouchard JF, N McNicoll, et al. Identification and characterization of a new growth hormone-releasing peptide receptor in the heart. Circ Res. 1999; 85: 796-802
38. Nagaya N, Uematsu M, Kojima M, et al. Chronic administration of ghrelin improves left ventricular dysfunction and attenuates development of cardiac cachexia in rats with heart failure. Circulation. 2001; 104:1430-1435
39. Amato G, Carella C, Fazio S, et al. Body composition, bone metabolism, heartstructure and function in growth hormone deficient adults before and after growth hormone replacement therapy at low doses. J Clin Endocrinol Metab. 1993; 77: 1671-1676
40. Fuller J, Mynett JR, Sugden PH. Stimulation of cardiac protein synthesis by insulin-like growth factors. Biochem J. 1992; 282: 85-90
41. Yang R, Bunting S, Gillett N, et al. Growth hormone improves cardiac performance in experimental heart failure. Circulation. 1995; 92: 262-267
42. Cittadini A, Stromer H, Katz SE, et al. Differential cardiac effects of growth hormone and insulin-like growth factor-1 in the rat: a combined in vivo and in vitro evaluation. Circulation. 1996; 93: 800-809
43. Osterziel KJ, Strohm O, Schuler J, et al. Randomised, double-blind, placebo-controlled trial of human recombinant growth hormone in patients with chronic heart failure due to dilated cardiomyopathy. Lancet. 1998; 351: 1233-1237
44. Isgaard J, Bergh CH, Caidahl K, et al. A placebo-controlled study of growth hormone in patients with congestive heart failure. Eur Heart J. 1998; 19: 1704-1711
45. Anker SD, Chua TP, Ponikowski P, et al . Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance in cardiac cachexia. Circulation. 1997; 96: 526-534
46. Niebauer J, Pflaum CD, Clark AL, et al. Deficient insulin-like growth factor I in chronic heart failure predicts altered body composition, anabolic deficiency, cytokine and neurohormonal activation. J Am Coll Cardiol. 1998; 32: 393-397
47. Itoh G, Tamura J, Suzuki M, et al. DNA fragmentation of human infarcted myocardial cells demonstrated by the nick end labeling method and DNA agarose gelelectrophoresis. Am J Pathol. 1995; 146: 1325-1331
48. Saraste A, Pulkki K, Kallajoki M, et al. Apoptosis in human acute myocardial infarction. Circulation.l997;95:320 -323
49. Narula J, Haider N, Virmani R, et al. Apoptosis in myocytes in end-stage heart failure. N Engl J Med. 1996;335:1182-1189
50. MacLellan WR, Schneider MD. Death by design: programmed cell death in cardiovascular biology and disease. Circ Res. 1997; 81:137-144
51. Haunstetter A, Izumo S. Apoptosis: basic mechanisms and implications for cardiovascular disease. Circ Res. 1998;82:1111—1129
52. Bisi G., Podio V, Valetto MR, et al. Cardiac effects of hexarelin in hypopituitary adults. Eur. J. Pharmacol. 1999 ; 381:31-38
53. Okumura H, Nagaya N, Enomoto M, et al. Vasodilatory effect of ghrelin, an endogenous peptide from the stomach. J Cardiovasc Pharmacol. 2002; 39: 779-783
54. Tivesten A, Bollano E, Caidahl K, et al. The growth hormone secretagogue hexarelin improves cardiac function in rats after experimental myocardial infarction. Endocrinology. 2000 ; 141:60-66
55. King MK, Gay D M, Pan LC, et al. Treatment with a growth hormone secretagogue in a model of developing heart failure: effects on ventricular and myocyte function. Circulation. 2001; 103:308-313
56. Gnanapavan S, Kola B, Bustin SA, et al. The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J Clin Endocrinol Metab. 2002; 87:2988
57. Papotti M, Ghe C, Cassoni P, et al. Growth hormone secretagogue binding sites in peripheral human tissues. J Clin Endocrinol Metab. 2000 ;85:3803-3807
58. Bodart V, Febbraio M, Demers A, et al. CD36 mediates the cardiovascular action of growth hormone-releasing peptides in the heart. Circ Res. 2002; 90:844-849
59. Katugampola SD, Pallikaros Z, Davenport AP. [125I-His(9)]-ghrelin, a novel radioligand for localizing GHS orphan receptors in human and rat tissue: up-regulation of receptors with athersclerosis. Br J Pharmacol. 2001; 134: 143-149
60. Pang JJ, Xu RK, Xu XB, et al. Hexarelin protects rat cardiomyocytes from angiotensin II-induced apoptosis in vitro. Am J Physio- Heart Circ Physiol. 2004; 286: H1063-1069
61. Chung ES, Perlini S, Aurigemma GP, et al. Effects of chronic adenosine uptake blockade on adrenergic responsiveness and left ventricular chamber function in pressure overload hypertrophy in the rat. J Hypertens 1998; 16:1813-1822
62. Douglas PS, Reichek N, Plappert T, et al. Comparison of echocardiographic methods for assessment of LV shortening and wall stress. J Am Coll Cardiol 1987; 9:945-951
63. Ramakrishnan N, Catravas GN. N-(2-Mercaptoethyl)-1,3-propanediamine (WR-1065) protects thymocytes from programmed cell death. J Immunol. 1992; 148: 1817-1821
64. Prigent P, Blanpied C, Aten J, et al. A safe and rapid method for analyzing apoptosis-induced fragmentation of DNA extracted from tissues or cultured cells. J mmunol Methods. 1993;160:139-140. Letter
65. Green DR, Reed JC. Mitochondria and apoptosis. Science. 1998;281:1309—1312
66. Leri A, Claudio PP, Li Q, et al. Stretch-mediated release of angiotensin II induces myocyte apoptosis by activating p53 that enhances the local renin-angiotensin system and decreases the Bcl-2-to-Bax protein ratio in the cell. J Clin Invest. 1998;101:1326 -1342
67. Leri A, Liu Y, Malhotra A, et al. Pacing-induced heart failure in dogs enhances theexpression of p53 and p53-dependent genes in ventricular myocytes. Circulation. 1998 ;97:194-203
68. Xia Z, Dickens M, Raingeaud J, et al. Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science. 1995; 270;1326-1331
69 . Ma XL, Kumar S, Gao F, et al. Inhibition of p38 mitogen-activated protein kinase decreases cardiomyocyte apoptosis and improves cardiac fuction after myocardial ischemia and reperfusion. Circulation. 1999; 99: 1685-1691
70. Cook SA, Sugden PH, Clerk A. Activation of c-Jun N-terminal kinases and p38-mitogen-activated protein kinases in human heart failure secondary to ischaemic heart diease. J Mol Cell Cardol. 1999; 31; 1429-1434
71. Gillespie Brown J, Fuller SJ, Bogoyevitch MA, et al. The mitogen-activated protein kinase kinase MEK1 stimulates a pattern of gene expression typical of the hypertrophic phenotype in rat ventricular cardiomyocytes. J Biol Chem. 1995; 270; 28092-28096
72. Davis RJ. The mitogen-activated protein kinase signal transduction pathway. J Biol Chem. 1993; 268;14553-14556
73. Wang Y, Huang S, Sah VP, et al. Cardiac muscle cell hypertrophy and apoptosis induced by distinct members of the p38 mitogen- activated protein kinase family. J Biol Chem. 1998; 273;2161-2168
74. Tajima M, Weinberg EO, Bartunek J, et al. Treatment with growth hormone enhances contractile reserve and intracellular calcium transients in myocytes from rats with postinfarction heart failure. Circulation. 1999; 99: 127-134
75. Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med. 1990; 322: 1561-1566
76. Lorell BH, Carabello BA. Left ventricular hypertrophy: pathogenesis, detection, and prognosis. Circulation. 2000; 102: 470-479
77. Baker KM, Booz GW and Dostal DE. Cardiac actions of angiotensin II: Role of an intracardiac renin-angiotensin system. Annu Rev Physiol. 1992; 54: 227 - 241
78. Lindpaintner K, Ganten D. The cardiac renin-angiotensinsystem, an appraisal of present experimental and clinical evidence. Circ Res. 1991; 68: 905 - 921
79. XinShou OY, Kyoko T, Katsuko K, et al. Protective Effect of Salvia miltiorrhiza on Angiotensin Il-Induced Hypertrophic Responses in Neonatal Rat Cardiac Cells. Jpn J Pharmacol. 2001; 87, 289 - 296
80. Wollert KC, Drexler H. The renin-angiotensin system and experimental heart failure. Cardiovasc Res. 1999; 43: 838 - 849
81. Haber HL, Powers ER, Gimple LW, et al. Intracoronary angiotensin IIconverting enzyme inhibition improves diastolic function in patients with hypertensive left ventricular hypertrophy. Circulation. 1994; 89: 2616 - 2625
82. Friedrich SP, Lorell BH, Rousseau MF, et al. Intracardiac angiotensinconverting enzyme inhibition improves diastolic function in patients with left ventricular hypertrophy due to aortic stenosis. Circulation. 1994; 90: 2761 - 2771
83. Sudhir K, MacGregor JS, Gupta M, et al. Effect of selective angiotensin II receptor antagonism and angiotensin converting enzyme inhibition on the coronary vasculature in vivo: intravascular twodimensional and Doppler ultrasound studies. Circulation. 1993; 87: 931-938
84. Sudhir K, Chou TM, Hutchison SJ et al: Coronary vasodilation induced by angiotensin-converting enzyme inhibition in vivo: differential contribution of nitric oxide and bradykinin in conductance and resistance arteries. Circulation. 1996; 93,1734-1739
85. Antony I, Lerebours G and Nitenberg A. Angiotensin-convertingenzyme inhibition restores flow-dependent and cold pressor test-induced dilations in coronary arteries of hypertensive patients. Circulation. 1996; 94: 3115 - 3122
86. Bowers CY, Momany F, Reynolds GA. Stucture-activity relationships of a synthetic pentapeptide that specifically release growth hormone in vitro. Endocrinology. 1980; 106:663-667
87. Wu D, Chen C, Zhang J, et al. Effects in vitro of new growth hormone releasing peptide (GHRP-1) on growth hormone secretion from ovine pituitary cells in primary culture. J Neuroendocrinol. 1994; 6:185-190
88. Wu D, Chen C, Katoh K, et al. The effects of GH-releasing peptide-2 (GHRP-2 or KP 102) on GH secretion from primary cultured ovine pituitary cells can be abolished by a specific GH-releasing factor (GHF) receptor antagonist. J Endocrinol. 1994; 140: R9-13
89. Deghenghi R, Cananzi MM, Torsello A, et al. GH-releasing activity of Hexarelin, a new growth hormone releasing peptide, in infant and adult rats. Life Sci. 1994; 54: 1321-1328
90. Naoki M, Masahiro S, Shoji O, et al. Molecular Mechanism of Angiotensin II Type I and Type II Receptors in Cardiac Hypertrophy of Spontaneously Hypertensive Rats. Hypertension. 1997; 30: 796-802
91. Hanford DS, Thuerauf DJ, Murray SF, et al. Brain natriuretic peptide is induced by al-adrenergic agonists as a primary response gene in cultured rat cardiac myocytes. J Biol Chem. 1994; 269: 26227-26233
92. Hasenfuss G. Alterations of calcium-regulatory proteins in heart failure. Cardiovasc Res. 1998; 37: 279-28993. De Gasparo M, Catt KJ, Inagami T, et al. International union of pharmacology: XXIII, the angiotensin II receptors. Pharmacol Rev. 2000; 52: 415-472
94. Bogoyevitch MA, Sugden PH. The role of protein kinases in adaptational growth of the heart. Int J Biochem Cell Biol. 1996; 28: 1-12
95. Olson EN, Molkentin JD. Prevention of cardiac hypertrophy by calcineurin inhibition: hope or hype? Circ Res. 1999; 84: 623-632
96. Sadoshima J, Izumo S. Signal transduction pathways of angiotensin II-induced c-fos gene expression in cardiac myocytes in vitro. Roles of phospholipids-derived second messengers. Circ Res. 1993; 73:424-438
97. Eguchi S, Numaguchi K, Iwasaki H, et al. Calcium-dependent epidermal growth factor receptor transactivation mediates the angiotensin II-induced mitogen-activated protein kinase activation in vascular smooth muscle cells. J Biol Chem. 1998; 273: 8890-8896.
98. Sadoshima J, Izumo S. Molecular characterization of angiotensin II-induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibrlblasts. Circ Res 1993; 73:413-423
99. Sadoshima J, Qiu Z, Morgan JP, et al. Angiotensin II and other hypertrophic stimuli mediated by G protein-coupled receptors activate tyrosine kinase, mitogen-activated protein kinase, and 90-kD S6 kinase in cardiac myocytes. J Biol Chem. 1996; 271: 33592-33597
100. Sadoshima J, Izumo S. The heterotrimeric Gq protein-coupled angiotensin II receptor activates p21ras via the tyrosine kinase-Shc-Grb2-Sos pathway in cardiac myocytes. EMBOJ. 1996;15:775-787
101. Walter G, Thomas YB, Dominic J, et al. Adenoviral-Directed Expression of the Type 1A Angiotensin Receptor Promotes Cardiomyocyte Hypertrophy via Transactivation of the Epidermal Growth Factor Receptor. Cir Res. 2002; 90: 135
102. Adams MA, Bobik A, Korner PI. Differential development of vascular and cardiac hypertrophy in genetic hypertension: relation to sympathetic function. Hypertension. 1989;14:191-202
103. Korner P, Bobik A, Oddie C, et al. Sympathoadrenal system is critical for structural changes in genetic hypertension. Hypertension. 1993;22:243-252
104. Baker KM, Booz GW, Dostal DE. Cardiac actions of angiotensin II: Role of an intracardiac renin-angiotensin system. Annu Rev Physiol. 1992; 54: 227 - 241
105. Schnkert H, Dzau VJ, Tang SS, et al. Increased rat cardiac angiotensin converting enzyme activity and mRNA expression, in pressure overload left ventricular hypertrophy: Effects on coronary resistance, contractility, and relaxation. J Clin Invest 1990; 86: 1913-1920
106. Linz W, Schoelkens BA, Ganten D. Converting enzyme inhibition specifically prevents the development and induces regression of cardiac hypertrophy in rats. Clin Exp Hypertens. 1989; 11: 1325-135011
107. Baker KM, Cherin MI, Wixon SK, et al. Renin-angiotensin system involvement in presure-overload cardiac hypertrophy in rats. Am J Physiol 1990; 259: H324-H332
108. Issei K. Molecular Mechanism of CardiacHypertrophy and Development. Jpn Circ J. 2001; 65: 353-358
109. Brondello JM, Brunet A, Pouyssegur J, et al. The dual specificity mitogen-activated protein kinase phosphatase-1 and -2 are induced by the p42/p44 MAPK cascade. J Biol Chem. 1997; 272:1368-1376
110. Booz GW, Baker KM. Role of typel and type2 angiotensin receptors in angiotensin II-induced cardiomyocyte hypertrophy. Hypertension. 1996; 28: 635-640
111. Van Kesteren CAM, Van Heugten HAA, Lamers JMJ, et al. angiotensin II mediated growth and antigrowth effects in cultured neonatal rat cardiac myocytes and fibroblasts. J Mol Cell Cardiol. 1997; 29: 2147-2157
112. Fischer TA, Singh K, O Hara DS, et al. Role of AT1 and AT2 receptors in regulation of MAPK and MKP-1 by ANG II in adult cardiac myocytes. Am J Physiol. 1998; 275: H906-H916
113. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993; 362:801-809
114. Ross R. Atherosclerosis: a inflammation disease. N Engl J Med. 1999; 340: 115-128
115. Zhang SH, Reddick RL, Piedrahita JA, et al. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science. 1992; 258: 468-471.
116. Fleckenstein KN, Kehel L, Bouayadi FE, et al. New model of atheosclerosis in insulin resistant sand rats: hypercholesterole mia combined with D_2 vitamin. Atherosclerosis. 2000: 150:55-61
117. Kramsch DM. Atherosclerosis progression/regression: lipoprotein and vessel wall. Atherosclerosis. 1995; 118: s29-36
118. Ross R. Cell biology of atherosclerosis. Annu Rev Physiol. 1995; 57: 791-804
119. Johnston CI. Biochemistry and pharmacology of the rennin-angiotensin system. Drugs. 1990; 39(Suppl 1): 21-31
120. Dzau VJ, Pratt RE, Gibbons GH. Angiotensin as local modulating factor in ventricular dysfunction and failure due to coronary artery disease. Drugs. 1994; 47(Suppl 4):1
121. Dzau VJ. Cell biology and genetics of angiotensin in cardiovascular disease. J??Hypertension. 1994; 12(Suppl 4):S3
122.张均田.现代药理实验方法。北京:北京医科大学.中国协和医科大学出版社,1998;1263-1271
123. Potter DD, Sobey CG, Tompkins PK, et al. Evidence that macrophages in atherosclerotic lesions contain angiotensin Ⅱ. Circulation. 1998; 98:800-807
124. Nickenig G, Jung O, Streholw K, et al. Hypercholesterolemia is associated with enhanced angiotensin ATl-receptor expression. Am J Physiol. 1997; 272: H2701-H 2707
125. Hernandez-Presa MA, Bustos C, Ortego M, et al. ACE inhibitor quinapril reduces the arterial expression of NF-kappa B-dependent proinfammatory factors but not of collagen I in a rabbit model of atherosclerosis. Am J Pathol. 1998; 153:1825-1837
126. Naftilan AJ, Pratt RE, Eldridge CS, et al. Angiotensin Ⅱ induces c-fos expression in smooth muscle cells via transcriptional control. Hypertension. 1989; 13:706-711
127. Kawahara Y, Sunako M, Tsuda, et al. Angiotensin Ⅱ induces expression of c-fos gene through protein kinase C activation and calcium ion mobilization in cultured vascular smooth muscle cells. Biochem Biophys Res Commun. 1988:150:52-59
128. Schieffer B, Drexler H, Ling BN, et al. G protein coupled receptors control vascular smooth muscle cell proliferation via pp60c-src and p21ras. Am J Physiol, 1997; 272:C2019-2030
129. Carey RM, Wang ZQ, Siragy HM. Role of the angiotensin type 2 receptor in regulation of blood pressure and renal function. Hypertension. 2000; 35 [part2]:155-163
130. Warnholtz A, Nickenig G, Schulz E, et al. Increased NADH-oxidase-mediated superoxide production in the early stages of atherosclerosis. Circulation. 1999; 99:2027-2033
131. Berry C, Hamiolton CA, Brosnan MJ, et al. Investigation into the sources of superoxide in human blood vessels: Angiotensin II increases superoxide production in human internal mammary arteries. Circulation. 2000, 101:2206-2212
132. Sckultz R, Triggle CR. Role of NO in vascular smooth muscle. Tips. 1994; 15:225-229
133. Daviet L, McGregor JL. Vascular biology of CD36: roles of this new adhesion molecule family in different disease states. Thromb Haemost. 1997;78:65-69
134. Endemann G, Stanton LW, Madden KS, et al. CD36 is a receptor for oxidized low density lipoprotein. J Biol Chem. 1993;268:11811-11816
135. Nozaki S, Kashiwagi H, Yamashita S, et al. Reduced uptake of oxidized low density lipoproteins in monocyte-derived macrophages from CD36-deficient subjects. J Clin Invest. 1995;96:1859-1865
136. Nakata A, Nakagawa Y, Nishida M, et al. CD36, a novel receptor for oxidized low-density lipoproteins, is highly expressed on lipid-laden macrophages in human atherosclerotic aorta. Arterioscler Thromb Vasc Biol. 1999;19:1333—1339
137. Feng J, Han J, Pearce SF, et al. Induction of CD36 expression by oxidized LDL and IL-4 by a common signaling pathway dependent on protein kinase C and PPAR- (?). J Lipid Res. 2000; 41:688-696
138. Febbraio M, Podrez EA, Smith JD,et al. Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice. J Clin Invest. 2000; 105:1049-1056
139. Zhong C; Shun I; St(?)phane P , et al. Troglitazone Inhibits Atherosclerosis in Apolipoprotein E-Knockout Mice.Pleiotropic Effects on CD36 Expression and HDLArteriosclerosis, Thrombosis, and Vascular Biology. 2001; 21: 372
1. Narula J, Haider N, Virmani R et al. Programmed myocyte death in end stage heart failure. N Engl J Med. 1996; 335: 1182-1189
2. Olivetti G, Abbi R, Quaini F, et al. Apoptosis in the failing human heart. N Engl J Med. 1997; 336: 1131-1141
3. Olivetti G, Quaini F, Sala R, et al. Acute myocardial infarction in humans is associated with the activation of programmed myocyte cell death in the surviving portion of the heart. J Mol Cell Cardiol. 1996; 28: 2005-2016
4. Teiger E, Dam T-V, Richard L, et al. Apoptosis in pressure overload-induced heart hypertrophy in the rat. J Clin Invest. 1996; 97: 2891-2897
5. Li Z, Bing OHL, Long X, et al. Increased cardiomyocyte apoptosis during transition to heart failure in the spontaneously hypertensive rat. Am J Physiol. 1997; 272: H2313-H2319
6. Cheng W, Kajstura J, Nitahara JA, et al. Programmed myocyte cell death affects the viable myocardium after infarction in rats. Exp Cell Res. 1996; 226: 316-327
7. Sharov VG, Sabbah HN, Shimoyama H, et al. Evidence of cardiocyte apoptosis in myocardium of dogs with chronic heart failure. Am J Pathol. 1996; 148:141—149
8. Hengartner MO. The biochemistry of apoptosis. Nature. 2000; 407:770-776
9. Reed JC. Mechanisms of apoptosis. Am J Pathol. 2000 ;157:1415-1430
10. Imai Y, Kimura T, Murakami A, et al. The CED-4-homologous protein FLASH is involved in Fas-mediated activation of caspase-8 during apoptosis. Nature. 1999 ; 398:777-85
11. Jiang X, Wang X. Cytochrome c promotes caspase-9 activation by inducing nucleotidebinding to Apaf-1. J Biol Chem. 2000; 275: 31199-312203
12. Hasegawa K, Iwai-kanai E,Sasayama S. Neurohormonal Regulation of Myocardial Cell Apoptosis during the Development of Heart failure. J Cellular Physio. 2001; 186: 11-18
13. Kajstura J, Cigola E, Malhotra A, et al. Angiotensin II induces apoptosis of adult ventricular myocytes in vitro. J Mol Cardiol. 1997; 29: 859-870
14. Cigola E, Kajstura J, Li B, et al. Angiotensin II activates programmed myocyte cell death in vitro. Exp Cell Res. 1997; 231: 363-371
15. Goussev A, Sharov VG, Shimoyama H, et al. Effects of ACE inhibition on cardiomyocyte apoptosis in dogs with heart failure. Am J Physiol. 1998; 275: H626-631
16. Adams JW, Sakata Y, Davis MG, et al. Proc. Enhanced Galphaq signaling: a common pathway mediates cardiac hypertrophy and apoptotic heart failure.Proc Natl Acad Sci U S A. 1998; 95: 10140-10145
17. Communal C, Singh K, Pimentel DR, et al. Norepinephrine stimulates apoptosis in adult rat ventricular myocytes by activation of the beta-adrenergic pathway. Circulation. 1998; 98: 1329-1334
18. Communal C, Colucci WS, Singh K. p38 mitogen-activated protein kinase pathway protects adult rat ventricular myocytes against beta -adrenergic receptor-stimulated apoptosis. Evidence for Gi-dependent activation. J Biol Chem. 2000 ; 275: 19395-19400
19. Zaugg M, Xu W, Lucchinetti E, et al. Circulation. Beta-adrenergic receptor subtypes differentially affect apoptosis in adult rat ventricular myocytes. Circulation. 2000 ; 102:344-350
20. Bisognano JD, Weinberger HD, Boglmeyer TJ, et al. Myocardial-directed overexpression of the human beta(l)-adrenergic receptor in transgenic mice. J Mol Cell Cardiol. 2000 ;32:817-830
21. Asai K, Yang GP, Geng YJ, et al. Beta-adrenergic receptor blockade arrests myocyte damage and preserves cardiac function in the transgenic G(salpha) mouse. J Clin Invest. 1999 ;104:551-558
22. Saito S, Hiroi Y, Zou Y, et al. beta-Adrenergic pathway induces apoptosis through calcineurin activation in cardiac myocytes. J Biol Chem. 2000; 275:34528 -34533
23. Xiao RP, Ji X, Lakatta EG. Functional coupling of the beta 2-adrenoceptor to a pertussis toxin-sensitive G protein in cardiac myocytes. Mol Pharmacol. 1995; 47: 322-329
24. Adams JW, Brown JH, G-proteins in growth and apoptosis: lessons from the heart. Oncogene. 2001; 20: 1626-1634
25. Cohen P. The search for physiological substrates of MAP and SAP kinases in mammalian cells. Trends Cell Biol. 1997;7: 353-361
26. Kumar A, Middleton A, ChambersTC, et al. Differential roles of extracellular signal-regulated kinase-1/2 and p38(MAPK) in interleukin-1beta- and tumor necrosis factor-alpha-induced low density lipoprotein receptor expression in HepG2 cells. J Biol Chem. 1998; 273:15742-15748
27. Schumann RR, Pfeil D, Lamping N et al. Lipopolysaccharide induces the rapid tyrosine phosphorylation of the mitogen-activated protein kinases erk-1 and p38 in cultured human vascular endothelial cells requiring the presence of soluble CD14. Blood. 1996; 87:2805-2814
28. Alessi DR, Cuenda A, Cohen P, et al. PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J Biol Chem.1995;270:27489-27494
29. Favata MF, Horiuchi KY, Manos EJ, et al. Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem. 1998;273: 18623-18632
30. Lee JC, laydon JT, McDonnell PC et al. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature. 1994; 372: 739-746
31. Dean JL, Brook M, Clark AR, et al. p38 mitogen-activated protein kinase regulates cyclooxygenase-2 mRNA stability and transcription in lipopolysaccharide-treated human monocytes. J Biol Chem. 1999;274: 264-269
32. Young P, McDonnell P, Dunnington D et al. Pyridinyl imidazoles inhibit IL-1 and TNF production at the protein level. Agents and Actions. 1993;39: C67-C69
33. Wang Y, Huang S, Sah VP, et al. Cardiac muscle cell hypertrophy and apoptosis induced by distinct members of the p38 mitogen-activated protein kinase family. J Biol Chem. 1998; 273: 2161-2168
34. Wang Y, Su B, Sah VP, et al. Cardiac hypertrophy induced by mitogen-activated protein kinase kinase 7, a specific activator for c-Jun NH2-terminal kinase in ventricular muscle cells. J Biol Chem. 1998 ; 273: 5423-5426
35. Sheng Z, Knowlton K, Chen J et al. CT-1 inhibition of cardiac myocyte apoptosis via a mitogen-activated protein kinase-dependent pathway. Divergence from downstream CT-1 signals for myocardial cell hypertrophy. J Biol Chem. 1997; 28: 272: 5783-5791
36. Baliga RR, Simmons WW,Sawyer DB et al. The role of MEK-MAPK-RSK pathway, PI3 kinase pathway and p70S~6K in neureguli induced growth of cardiac myocytes. Circulation. 1997; 96:1362
37. Zechner D, Craig R, Hanford DS et al. MKK6 activates myocardial cell NF-kB and inhibits apoptosis in a p38 mitogen-activated protein kinase- dependent manner. J BiolChem. 1998;273:8232-8239
38. Donehower LA, Harvey M, Slagle BL et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumors. Nature. 1992; 356:215-221.
39. Sharov VG, Sabbah HN, Shimoyama H et al. Evidence of cardiocyte apoptosis in myocardium of dogs with chronic heart failure. Am J Pathol. 1996; 148: 141-149
40. Sabbah HN, Shimoyama H, Kono T, et al. Effects of long-term monotherapy with enalapril, metoprolol, and digoxin on the progression of left ventricular dysfunction and dilation in dogs with reduced ejection fraction. Circulation. 1994; 89: 2852-2859
41. Pierzchalski P, Reiss K, Cheng W, et al. p53 Induces myocyte apoptosis via the activation of the renin-angiotensin system. Exp Cell Res. 1997; 234: 57-65
42. Schumann H, Bartling B, Rueckschloss et al. Expression of the apoptosis- mediating ligand TRAIL and its death domain receptors DR4, DR5 and decoy receptor DcR1 in normal and failing human myocardium. Circulation. 1998; Suppll: 1-361
43. Hockenbery D, Nunez G, Milliman C, et al. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature. 1990; 348:334-336
44. Allsopp TE, Wyatt S, Paterson HF, et al. The proto-oncogene bcl-2 can selectively rescue neurotrophic factor-dependent neurons from apoptosis. Cell. 1993; 73: 295- 307
45. Cheng W, Kajstura J, Nitahara JA, et al. Programmed myocyte cell death affects the viable myocardium after infarction in rats. Exp Cell Res. 1996 ;226:316 -327
46. Kirshenbaum LA, de Moissac D. The bcl-2 gene product prevents programmed cell death of ventricular myocytes. Circulation. 1997 ;96:1580-1585
47. de Moissac D, Mustapha S, Greenberg AH, et al. Bcl-2 activates the transcriptionfactor NFkappaB through the degradation of the cytoplasmic inhibitor IkappaBalpha. J Biol Chem. 1998; 273:23946-23951
48. Leri A, Claudio PP, Li Q, et al. Stretch-mediated release of angiotensin II induces myocyte apoptosis by activating p53 that enhances the local renin-angiotensin system and decreases the Bcl-2-to-Bax protein ratio in the cell. J Clin Invest. 1998; 101:1326-1342
49. Condorelli G, Morisco C, Stassi G, et al. Increased cardiomyocyte apoptosis and changes in proapoptotic and antiapoptotic genes bax and bcl-2 during left ventricular adaptations to chronic pressure overload in the rat. Circulation. 1999; 99:3071-3078
50. Narula J, Virmani R, Ballestster M. Heart failure pathogenesis and treatment. Martin Dunitz. 2002, 304
51. Bowers C Y, Momany F, Reynolds GA. Stucture-activity relationships of a synthetic pentapeptide that specifically release growth hormone in vitro. Endocrinology. 1980; 106:663-667
52. Wu D, Chen C, Zhang J, et al. Effects in vitro of new growth hormone releasing peptide (GHRP-1) on growth hormone secretion from ovine pituitary cells in primary culture. J Neuroendocrinol. 1994; 6:185-190
53. Wu D, Chen C, Katoh K, et al. The effects of GH-releasing peptide-2 (GHRP-2 or KP 102) on GH secretion from primary cultured ovine pituitary cells can be abolished by a specific GH-releasing factor (GHF) receptor antagonist. J Endocrinol. 1994; 140: R9-13
54. Deghenghi R, Cananzi MM, Torsello A, et al. GH-releasing activity of Hexarelin, a new growth hormone releasing peptide, in infant and adult rats. Life Sc. 1994; 54:1321-1328
55. Smith RG, Cheng K, Schoen WR, et al. a nonpeptidyl growth hormone secretagogue. Science. 1993; 260:1640-1643
56. Jacks T, Smith R, Judith F, et al. MK-0677, a potent, novel, orally active growth hormone (GH) secretagogue: GH, insulin like growth factor I, and other hormone responses in beagles. Endocrinology. 1996; 137:5284-5289
57. Papotti M, Ghe C, Cassoni P, et al. Growth hormone secretagogue binding sites in peripheral human tissues. J Clin Endocrinol Metab. 2000; 85: 3803-3807
58. Bodart V, Bouchard JF, McNicoll N, et al. Identification and characterization of a new growth hormone-releasing peptide receptor in the heart. Circ Res. 1999; 85:796-802
59. Palyha OC, Feighner SD, Tan CP, et al. Ligand activation domain of human orphan growth hormone (GH) secretagogue receptor (GHS-R) conserved from Pufferfish to humans. Mol Endocrinol. 2000; 14: 160-169
60. Muccioli G, Broglio F, Valetto MR, et al. Growth hormone-releasing peptides and the cardiovascular system. Ann Endocrinol. (Paris) 2000; 61: 27-31
61. Locatelli V, Rossoni G, Schweiger F, et al. Growth hormone-independent cardioprotective effects of hexarelin in the rat. Endocrinology. 1999; 140: 4024-4031
62. Bisi G, Podio V, Valetto MR, et al. Acute cardiovascular and hormonal effects of GH and hexarelin, a synthetic GH-releasing peptide, in humans. J Endocrinol Invest. 1999;22:266-272
63. Filigheddu N, Fubini A, Baldanzi G, et al. Hexarelin protects H9c2 cardiomyocytes from doxorubicin-induced cell death. Endocrine 2001, 14: 113-119
64. Baldanzi G, Filigheddu N, Cutrupi S, et al. Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/AKT. J Cell Biol. 2002; 159: 1029-37
65. Ekhterae D, Lin Z, Lundberg MS, et al. ARC inhibits cytochrome c release from mitochondria and protects against hypoxia-induced apoptosis in heart-derived H9c2 cells. Circ Res. 1999; 85: E70-E77
66. Wang L, Ma W, Markovich R, et al. Regulation of cardiomyocyte apoptotic signaling by insulin-like growth factor I. Circ Res. 1998; 83: 516-522
67. Wang L, Ma W, Markovich R, et al. Insulin-like growth factor I modulates induction of apoptotic signaling in H9C2 cardiac muscle cells. Endocrinology 1998; 139: 1354-1360
68. Pettersson I, Muccioli G, Granata R, et al. Natural (ghrelin) and synthetic (hexarelin) GH secretagogues stimulate H9c2 cardiomyocyte cell proliferation. J Endocrinol. 2002; 175:201-209
69. Pang JJ, Xu RK, Xu XB, Cao JM, Ni C, Zhu WL, Asotra K, Chen MC, Chen C. Hexarelin protects rat cardiomyocytes from angiotensin Il-induced apoptosis in vitro. Am J Physio- Heart Circ Physiol. 2004; 286: H1063-1069
70. Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med. 1990; 322: 1561-1566
71. Lorell BH, Carabello BA. Left ventricular hypertrophy: pathogenesis, detection, and prognosis. Circulation. 2000; 102: 470-479
72. Hongo M, Ryoke T, Ross J. Animal models of heart failure: Recent developments and perspectives. Trends Cardiovasc Med. 1997;7: 161-167
73. Chien KR, Knowlton KU, Zhu H, Chien S. Regulation of cardiac gene expression during myocardial growth and hypertrophy: molecular studies of an adaptive physiologic response. FASEB J. 1991; 5: 3037-3046
74. Sugden PH, Clerk A. Cellular mechanisms of cardiac hypertrophy. JMol Med. 1998; 76:725-746
75. Hanford DS, Thuerauf DJ, Murray SF, et al. Brain natriuretic peptide is induced by a1-adrenergic agonists as a primary response gene in cultured rat cardiac myocytes. J Biol Chem. 1994; 269: 26227-26233
76. Hasenfuss G. Alterations of calcium-regulatory proteins in heart failure. Cardiovasc Res. 1998; 37: 279-289
77. Sugden P. Signaling in myocardial hypertrophy life after calcineurin? Circ Res. 1999; 84: 633-646
78. Adams JW, Brown JH. G-proteins in growth and apoptosis: lessons from the heart. Oncogene. 2001; 20: 1626-1634
79. Adams JW, Pagel AL, Means CK, et al. Cardiomyocyte apoptosis induced by Galphaq signaling is mediated by permeability transition pore formation and activation of the mitochondrial death pathway. Circ Res. 2000; 87: 1180-1187
80. Takeishi Y, Ping P, Bolli R, et al. Transgenic overexpression of constitutively active protein kinase C epsilon causes concentric cardiac hypertrophy. Circ Res. 2000; 86: 1218-1223
81. Sugden PH, Clerk A. "Stress-responsive" mitogen-activated protein kinases (c-Jun N-terminal kinases and p38 mitogen-activated protein kinases) in the myocardium. Circ Res. 1998; 83: 345-352
82. Varma DR, Deng X. Cardiovascular alpha 1-adrenoceptor subtypes: functions and signaling. Can J Physiol Pharmacol. 2000; 78: 267-292
83. Theroux TL, Esbenshade TA, Peavy RD, et al. Coupling efficiencies of human alpha 1-adrenergic receptor subtypes: titration of receptor density and responsiveness with inducible and repressible expression vectors.Mol Pharmacol. 1996; 50: 1376-1387
84. McWhinney C, Wenham D, Kanwal S, et al. Constitutively active mutants of the alpha(1a)- and the alpha(1b)-adrenergic receptor subtypes reveal coupling to different signaling pathways and physiological responses in rat cardiac myocytes. J Biol Chem. 2000; 275: 2087-2097
85. Zhu YC, Zhu YZ, Gohlke P, et al. Effects of angiotensin-converting enzyme inhibition and angiotensin II AT1 receptor antagonism on cardiac parameters in left ventricular hypertrophy. Am J Cardiol. 1997; 80 : 110A-117A
86. Paradis P, Dali-Youcef N, Paradis FW, et al. Overexpression of angiotensin II type I receptor in cardiomyocytes induces cardiac hypertrophy and remodeling. Proc Natl Acad Sci U S A. 2000; 97:931 -936
87. Miyauchi T, Goto K. Heart failure and endothelin receptor antagonists. Trends Pharmacol Sci. 1999; 20: 210-217
88. Widmann C, Gibson S, Jarpe MB, Johnson GL, Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiol Rev. 1999; 79:143-180.
89. Sugden PH, Clerk A. "Stress-responsive" mitogen-activated protein kinases (c-Jun N-terminal kinases and p38 mitogen-activated protein kinases) in the myocardium. Circ Res. 1998; 24:345-352
90. Rapacciuolo A, Esposito G, Caron K, et al. Important role of endogenous norepinephrine and epinephrine in the development of in vivo pressure-overload cardiac hypertrophy. J Am Coll Cardiol. 2001; 38: 876-882
91. Takeishi Y, Huang Q, Abe Ji, et al. Src and multiple map kinase activation in cardiac hypertrophy and congestive heart failure under chronic pressure-overload: comparison with acute mechanical stretch. J Mol Cell Cardiol. 2001; 33: 1637 -1648
92. Liang F, Lu S, Gardner DG. Endothelin-dependent and -independent components of strain-activated brain natriuretic peptide gene transcription require extracellular signal regulated kinase and p38 mitogen-activated protein kinase. Hypertension. 2000; 35: 188-192
93. Kodama H, Fukuda K, Pan J, et al. Significance of ERK cascade compared with JAK/STAT and PI3-K pathway in gp130-mediated cardiac hypertrophy. Am J Physiol Heart Circ Physiol. 2000; 279: H1635-H1644
94. Yue TL, Gu JL, Wang C, et al. Extracellular signalregulated kinase plays an essential role in hypertrophic agonists, endothelin-1 and phenylephrine-induced cardiomyocyte hypertrophy. J Biol Chem. 2000; 275: 37895-37901
95. Ueyama T, Kawashima S, Sakoda T, et al. Requirement of activation of the extracellular signal-regulated kinase cascade in myocardial cell hypertrophy. J Mol Cell Cardiol. 2000; 32: 947-960
96. Thorburn J, Frost JA, Thorburn A. Mitogen-activated protein kinases mediate changes in gene expression, but not cytoskeletal organization associated with cardiac muscle cell hypertrophy. J Cell Biol. 1994; 126: 1565-1572
97. Thorburn J, McMahon M, Thorburn A. Raf-1 kinase activity is necessary and sufficient for gene expression changes but not sufficient for cellular morphology changes associated with cardiac myocyte hypertrophy. J Biol Chem. 1994; 269: 30580-30586
98. Choukroun G, Hajjar R, Kyriakis JM, et al. Role of the stress-activated protein kinases in endothelininduced cardiomyocyte hypertrophy. J Clin Invest. 1998; 102: 1311-1320
99. Liang Q, Wiese RJ, Bueno OF, et al. The transcription factor GATA4 is activated by extracellular signal-regulated kinase 1- and 2-mediated phosphorylation of serine 105 in cardiomyocytes. Mol Cell Biol. 2001; 21: 7460-7469
100.Morimoto T, Hasegawa K, Kaburagi S, et al. Phosphorylation of GATA-4 is involved in 1- adrenergicagonist -responsive transcription of the endothelin-1 gene in cardiac myocytes. J Biol Chem. 2000; 275: 13721-13726
101.Ip YT, Davis RJ. Signal transduction by the c-Jun N-terminal kinase(JNK)-from inflammation to development. Curr Opin Cell Bio. 1998; 10:205-219
102.Komuro I, Kudo S, Yamazaki T, et al. Mechanical strech activates the stress-activated protein kinases in cardiac myocyte. FASEB J. 1996;10; 631-636
103.Kudoh S, Komuro I, Mizuno T, et al. Angiotension II stimulates c-Jun NH2- terminal kinase in cultured cardiac myocytes of neonatal rats. Circ Res. 1997; 80: 139-146
104.Yamazaki T, Komuro I, Kudoh S, et al. Mechanical stress activates protein kiase cascade of phosphorylation in neonatal rat cardiac myocytes. J Clin Invest.1995; 96: 438-446
105.Ichijo H, Nishida E, Irie K, et al. Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science. 1997; 275: 90-94
106.New L, Han J. The p38MAP kinase pathway and its biological function. Trends Cardiovasc Med. 1998; 8: 220-228
107.Bozkurt B, Kribbs SB, Clubb FJ Jr, et al. Pathphysiologically relevant concentrations of tumor necrosis factor-a promote progressive left ventricular dysfunction and remodeling in rats. Circulation. 1998; 97: 1382-1391
108.Jiang Y, Chen C, Li Z, et al. Characterization of the structure and function of a new mitogen-activated protein kinase (p38beta). J Biol Chem. 1996; 271: 17920-17926
109.Takeda N, Nagano M, Narajin S. The hypertrophied heart. Kluwer Academin Publishers. 2000, 111
110.Guerini D. Calcineurin: not just a simple protein phosphatase. Biochem Biophys Res Commun. 1997; 235: 271-275
111.Klee CB, Ren H, Wang X. Regulation of the calmodulin-stimulated protein phosphatase, calcineurin. J Biol Chem. 1998; 273: 13367-13370
112.Hasegawa K, Lee SJ, Jobe SM, et al. Cis-acting sequences that mediate induction of beta- myosin heavy chain gene expression during left ventricular hypertrophy due to aortic constriction. Circulation. 1997; 96: 3943-3953
113.Molkentin JD, Lu JR, Antos CL, et al. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell. 1998, 93:7543-7548
114.Sussman MA, Lim HW, Gude N, et al. Prevention of cardiac hypertrophy in mice by calcineurin inhibition. Science. 1998; 281:1690-1693
115.Juliano RL, Haskill S. Signal transduction from the extracellular matrix. J Cell Biol. 1993; 120:577-585
116.Hynes ro. Integrins: versatility, modulation, and signaling in cell adhesion. Cell. 1992; 69:11-25
117.Mackay DJ, Hall A. Rho GTPases. J Biol Chem. 1998; 273:20685-20688
118.Aikawa R, Komuro I, yamazaki T, et al. Rho family small G proteins play critical roles in mechanical stress-induced hypertrophic responses in cardiacmyocytes. Circ Res. 1999; 84:458-466
119.Thorburn J, Xu S, Thorburn A. MAP kinase- and Rho-dependent signals interact to regulate gene expression but not actin morphology in cardiac muscle cells. EMBO J. 1997;16:1888-1900
120.Sah VP, Hoshijima M, Chien KR, et al. Rho is required for Galphaq and alphal-adrenergic receptor signaling in cardiomyocytes. Dissociation of Ras and Rho pathways. J Bio Chem. 1996; 271:31185-31190
121.Chien KR, Zhu H, Knowlton KU, et al. Transcriptional regulation during cardiac growth and development. Annu Rev Physiol. 1993; 55: 77-95
122.Komuro I, Yazaki Y. Control of cardiac gene expression by mechanical stress. Annu Rev Physiol. 1993; 55: 55-75
123.Sadoshima J, Izumo S. The cellular and molecular response of cardiac myocytes to mechanical stress. Annu Rev Physiol. 1997; 59: 551-571
124.Shimkets RA, Lowe DG, Tai JT, et al. Gene expression analysis by transcript profiling coupled to a gene database query. Nat Biotechnol. 1999; 17: 798-1003
125.Friddle CJ, Koga T, Rubin EM, et al. Expression profiling reveals distinct sets of genes altered during induction and regression of cardiac hypertrophy. Proc Natl Acad Sci U S A. 2000; 97: 6745-6750
126.Bruneau BG. Transcriptional regulation of vertebrate cardiac morphogenesis. Circ Res. 2002; 90: 509-519
127.Patient RK, McGhee JD. The GATA family (vertebrates and invertebrates). Curr Opin Genet Dev. 2002; 12:416-422
128.Molkentin JD. The zinc finger-containing transcription factors GATA-4, -5, and -6: ubiquitously expressed regulators of tissue-specific gene expression. J Biol Chem. 2000; 275: 38949-38952
129.Liang Q, Molkentin JD. Divergent signaling pathways converge on GATA4 to regulate cardiac hypertrophic gene expression. J Mol Cell Cardiol. 2002; 34: 611-616
130.Hasegawa K, Lee SJ, Jobe SM, et al. Cis-acting sequences that mediate induction of β-myosin heavy chain gene expression during left ventricular hypertrophy due to aortic constriction. Circulation. 1997; 96: 3943-3953
131 .Herzig TC, Jobe SM, Aoki H, et al. Angiotensin II type la receptor gene expression in the heart: AP-1 and GATA-4 participate in the response to pressure overload. Proc Natl Acad Sci U S A. 1997; 94: 7543-7548
132.Charron F, Tsimiklis G, Arcand M, et al. Tissue-specific GATA factors are transcriptional effectors of the small GTPase RhoA. Genes Dev. 2001; 15: 2702-2719
133.Morimoto T, Hasegawa K, Kaburagi S, et al. Phosphorylation of GATA-4 is involved in a-adrenergic agonist-responsive transcription of the endothelin-1 gene in cardiac myocytes. J Biol Chem. 2000; 275: 13721-13726.
134. Liang Q, Wiese RJ, Bueno OF, et al. The transcription factor GATA4 is activated by extracellular signal-regulated kinase 1 - and 2-mediated phosphorylation of serine 105 in cardiomyocytes. Mol Cell Biol. 2001; 21: 7460-7469
135.Kerkela R, Pikkarainen S, Majalahti PT, et al. Distinct roles of mitogen-activated protein kinase pathways in GATA-4 transcription factor-mediated regulation of B-type natriuretic peptide gene. J Biol Chem. 2002; 277: 13752-3760
136.Dai YS, Markham BE. p300 functions as a coactivator of transcription factor GATA-4. J Biol Chem. 2001; 276: 37178-37185
137.Belaguli NS, Sepulveda JL, Nigam V, et al. Cardiac tissue enriched factors serum response factor and GATA-4 are mutual coregulators. Mol Cell Biol. 2000; 20: 7550-7558138. Morin S, Charron F, Robitaille L, et al. GATA-dependent recruitment of MEF2 proteins to target promoters. EMBO J. 2000; 19:2046-2055
139. Black BL, Olson EN. Transcriptional control of muscle development by myocyte enhancer factor-2 (MEF2) proteins. Ann Rev Cell Dev Biol. 1998; 14:167-196
140. McKinsey TA, Zhang CL, Olson EN. MEF2: a calcium-dependent regulator of cell division, differentiation and death. Trends Biochem Sci. 2002; 27:40-47
141. Liu ZP, Nakagawa O, Nakagawa M, et al. CHAMP, a novel cardiac-specific helicase regulated by MEF2C. Dev Biol. 2001; 234:497-509
142. Zhu H, Garcia AV, Ross RS, et al. A conserved 28-base-pair element (HF-1) in the rat cardiac myosin light-chain-2 gene confers cardiac-specific and α-adrenergic-inducible expression in cultured neonatal rat myocardial cells. Mol Cell Biol. 1991; 11: 2273-2281
143. Han J, Molkentin JD. Regulation of MEF2 by p38 MAPK and its implication in cardiomyocyte biology. Trends Cardiovasc Med. 2000; 10:19-22
144. Kato Y, Kravchenko VV, Tapping RI, et al. BMK1/ERK5 regulates serum-induced early gene expression through transcription factor MEF2C. EMBO J. 1997; 16: 7054-7066
145. Yang CC, Ornatsky OI, McDermott JC, et al. Interaction of myocyte enhancer factor 2 (MEF2) with a mitogen-activated protein kinase, ERK5/BMK1. Nucleic Acids Res. 1998; 26:4771-4777
146. Tamir Y, Bengal E. Phosphoinositide 3-kinase induces the transcriptional activity of MEF2 proteins during muscle differentiation. J Biol Chem. 2000; 275:34424-34432.
147. Frey N, McKinsey TA, Olson EN. Decoding calcium signals involved in cardiac growth and function. Nat Med. 2000; 6:1221-1227
148.Passier R, Zeng H, Frey N, et al. CaM kinase signaling induces cardiac hypertrophy and activates the MEF2 transcription factor in vivo. J Clin Invest. 2000; 105: 1395-1406
149.Chen CY, Schwartz RJ. Identification of novel DNA binding targets and regulatory domains of a murine tinman homeodomain factor, nkx-2.5. J Biol Chem. 1995;270:15628-15633
150.Tanaka M, Chen Z, Bartunkova S, et al. The cardiac homeobox gene Csx/Nkx2.5 lies genetically upstream of multiple genes essential for heart development. Development. 1999;126:1269-1280
151.Thompson JT, Rackley MS, O'Brien TX. Upregulation of the cardiac homeobox gene Nkx2-5 (CSX) in feline right ventricular pressure overload. Am J Physiol. 1998; 274: H1569-1573
152. Saadane N, Alpert L, Chalifour LE. Expression of immediate early genes, GATA-4, and Nkx-2.5 in adrenergic-induced cardiac hypertrophy and during regression in adult mice. Br J Pharmacol. 1999; 127: 1165-1176.
153. Akazawa H, Komuro I. Roles of Cardiac Transcription Factors in Cardiac Hypertrophy. Cir Res. 2003; 92: 1079-1088
154.Srivastava D. HAND proteins: molecular mediators of cardiac development and congenital heart disease. Trends Cardiovasc Med. 1999; 9: 11-18
155.Srivastava D, Thomas T, Lin Q, et al. Regulation of cardiac mesodermal and neural crest development by the bHLH transcription factor, dHAND. Nat Genet. 1997; 16: 154-160
156.Thattaliyath BD, Livi CB, Steinhelper ME, et al. HAND1 and HAND2 are expressed in the adult-rodent heart and are modulated during cardiac hypertrophy. Biochem Biophys Res Commun. 2002; 297: 870-875
157.Dai YS, Cserjesi P, Markham BE, et al. The transcription factors GATA4 and dHAND physically interact to synergistically activate cardiac gene expression through a p300-dependent mechanism. J Biol Chem. 2002; 77: 4390-4398