中介素在心血管系统的研究进展_West China Medical Journal

Authors：

吴凯 ^1,2 , 王斯 ¹ ,  陈晓平 ¹ , 高音 ²

Corresponding author：

陈晓平, Email: wukaidewenzang@163.com

Keywords：

中介素; 冠状动脉粥样硬化性心脏病; 降钙素相关肽; 降钙素受体样受体/受体活化修饰蛋白复合物; G蛋白耦联受体

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【摘要】　中介素（intermedin，IMD）又称肾上腺髓质素2，是降钙素基因相关肽超家族的一员。IMD能够无选择性作用于降钙素受体样受体/受体活化修饰蛋白复合物，通过受体复合物上G蛋白的变构，激活下游的效应酶及离子通道，再进一步发挥生物学效应。IMD的作用广泛，其对血管的作用主要包括血管生成作用、外周血管扩张作用、中枢升压作用及抗血管钙化作用；其对心脏的作用主要包括正性肌力作用、正性频率作用、抗心肌肥厚的作用等。

Citation： 吴凯,王斯,陈晓平,高音. 中介素在心血管系统的研究进展. West China Medical Journal, 2011, 26(8): 1250-1255. doi: Copy

1.	Roh J, Chang CL, Bhalla A, et al. Intermedin is a calcitonin/CGRP family peptide acting through the calcitonin receptor-like receptor activity modifying protein receptor complexes[J]. J Biol Chem, 2004, 279(8): 7264-7274.
2.	Takei Y, Inoue K, Ogoshi M, et al. Identification of novel adrenomedullin in mammals: a potent cardiovascular and renal regulator[J]. Febs Letters, 2004, 556(1-3): 53-58.
3.	周芸, 李荣山. 中介素的生物学效应研究进展[J]. 医学综述, 2010, 16(1): 13-16.
4.	Squire LR. Encyclopedia of Neuroscience[M]. Oxford: Academic Press, 2009: 509-552.
5.	Yang JH, Jia YX, Pan CS, et al. Effects of intermedin1-53 on cardiac function and ischemia/reperfusion injury in isolated rat hearts[J]. Biochem Biophys Res Commun, 2005, 327(3): 713-719.
6.	Ren YS, Yang JH, Zhang J, et al. Intermedin 1-53 in central nervous system elevates arterial blood pressure in rats[J]. Peptides, 2006, 27(1): 74-79.
7.	Taylor MM, Bagley SL, Samson WK. Intermedin/adrenomedullin-2 acts within central nervous system to elevate blood pressure and inhibit food and water intake[J]. Am J Physiol Regul Integr Comp Physiol, 2005, 288(4): 919-927.
8.	McLatchie LM, Fraser NJ, Main MJ, et al. RAMPs regulate the transport and ligand specifity of the calcitonin-receptor-liker receptor[J]. Nature, 1998, 393(6683): 332-339.
9.	Dennis T, Fournier A, Cadieaux A, et al. hCGRP8-37: a CGRP antagonist revealing CGRP receptor heterogeneity in the brain and periphery[J]. J Pharmacol Exp Ther, 1990, 254(1): 123-128.
10.	Poyner DR, Sexton PM, Marshall I, et al. IUPHAR XXXII. The mammalian calcitonin gene-related peptides, adrenomedullin, amylin, and calcitonin receptors[J]. Pharmacol Rev, 2002, 54(2): 233-246.
11.	Hay DL, Howitt SG, Conner AC, et al. CL/RAMP2 and CL/RAMP3 produce pharmacologically distinct adrenomedullin receptors; a comparison of effects of adrenomedullin 22-52, CGRP8-37 and BIBN4096BS[J]. Br J Pharmacol, 2003, 140(3): 477-486.
12.	Hay DL, Conner AC, Howitt SG, et al. The pharmacology of CGRP-responsive receptors in cultured and transfected cells[J]. Peptides, 2004, 25(11): 2019-2026.
13.	Hay DL, Christopoulos G, Christopoulos A, et al. Pharmacological discrimination of calcitonin receptor: receptor activity modifying protein complexes[J]. Mol Pharmacol, 2005, 67(5): 1655-1665.
14.	Morimoto R, Satoh F, Murakami O, et al. Expression of adrenomedullin 2/intermedin in human brain, heart, and kidney[J]. Peptides, 2007, 28(5): 1095-1103.
15.	Totsune K, Takahashi K, Mackenzie HS, et al. Increased gene expression of adrenomedullin and adrenomedullin-receptor complexes, receptor-activity modifying protein(RAMP)2 and calcitonin-receptor-like receptor(CRLR) in the hearts of rats with congestive heart failure[J]. Clin Sci (Lond), 2000, 99(6):541-546.
16.	Cueille C, Pidoux E, de Vernejoul MC, et al. Increased myocardial expression of RAMP1 and RAMP3 in rats with chronic heart failure[J]. Biochem Biophys Res Commun, 2002, 294(2): 340-346.
17.	Zhao Y, Bell D, Smith LR, et al. Differential expression of components of the cardiomyocyte adrenomedullin/intermedin receptor system following blood pressure reduction in nitric oxide-deficient hypertension[J]. J Pharmacol Exp Ther, 2006, 316(3): 1269-1281.
18.	Hagner S, Stahl U, Knoblauch B, et al. Calcitonin receptor-like receptor: identification and distribution in human peripheral tissues[J]. Cell Tissue Res, 2002, 310(1): 41-50.
19.	Cottrell GS, Roosterman D, Marvizon JC, et al. Localization of calcitonin receptor-like receptor and receptor activity modifying protein 1 in enteric neurons, dorsal root ganglia, and the spinal cord of the rat[J]. J Comp Neurol, 2005, 490(3): 239-255.
20.	Oliver KR, Wainwright A, Edvinsson L, et al. Immunohistochemical localization of calcitonin receptor-like receptor and receptor activity-modifying proteins in the human cerebral vasculature[J]. J Cereb Blood Flow Metab, 2002, 22(5): 620-629.
21.	Autelitano DJ, Ridings R. Adrenomedullin signalling in cardiomyocytes is dependent upon CRLR and RAMP2 expression[J]. Peptides, 2001, 22(11): 1851-1857.
22.	Nagae T, Mukoyama M, Sugawara A, et al. Rat receptor-activity-modifying proteins(RAMPs) for adrenomedullin/CGRP receptor: cloning and upregulation in obstructive nephropathy[J]. Biochem Biophys Res Commun, 2000, 270(1): 89-93.
23.	Kamitani S, Asakawa M, Shimekake Y, et al. The RAMP2/CRLR complex is a functional adrenomedullin receptor in human endothelial and vascular smooth muscle cells[J]. FEBS Lett, 1999, 448(1): 111-114.
24.	Christopoulos A, Christopoulos G, Morfis M, et al. Novel receptor partners and function of receptor activity-modifying proteins[J]. J Biol Chem, 2003, 278(5): 3293-3297.
25.	Tfelt-Hansen J, Hansen JL, Smajilovic S, et al. Calcium receptor is functionally expressed in rat neonatal ventricular cardiomyocytes[J]. Am J Physiol, 2006, 290(3): 1165-1171.
26.	Kuwasako K, Cao YN, Nagoshi Y, et al. Characterization of the human calcitonin gene-related peptide receptor subtypes associated with receptor activity-modifying proteins[J]. Mol Pharmacol, 2004, 65(1): 207-213.
27.	Jia YX, Yang JH, Pan CS, et al. Intermedin1-53 protects the heart against isoproterenol-induced ischemic injury in rats[J]. Eur J Pharmacol, 2006, 549(1-3): 117-123.
28.	Charles CJ, Rademaker MT, Richards AM. Hemodynamic, hormonal, and renal actions of adrenomedullin-2 in normal conscious sheep[J]. Endocrinology, 2006, 147(4): 1871-1877.
29.	Dong F, Taylor MM, Samson WK, et al. Intermedin(adrenomedullin-2) enhances cardiac contractile function via a protein kinase C-and protein kinase A-dependent pathway in murine ventricular myocytes[J]. J Appl Physiol, 2006, 101(3): 778-784.
30.	Yang JH, Pan CS, Jia YX, et al. Intermedin 1-53 activates l-arginine/nitric oxide synthase/nitric oxide pathway in rat aortas[J]. Biochem Biophys Res Commun, 2006, 341(2): 567-572.
31.	Doganci S, Yildirim V, Bolcal C, et al. Intermedin(IMD/AM2) dilates the pig coronary vascular bed through release of nitric oxide[J]. Turkish J Thorac Cardiovasc Surg, 2011, 19(2): 242-246.
32.	Kandilci HB, Gumusel B, Lippton H. Intermedin/adrenomedullin-2(IMD/AM2) relaxes rat pulmonary arterial rings in a nitric oxide and endothelial-dependent manner[J]. FASEB J, 2007, 21(4): 979.14.
33.	Smith RS Jr, Gao L, Bledsoe G, et al. Intermedin is a new angiogenic growth factor[J]. Am J Physiol Heart Circ Physiol, 2009, 297(3): 1040-1047.
34.	Abdelrahman AM, Pang CC. Effect of intermedin/adrenomedullin-2 on venous tone in conscious rats[J]. Naunyn Schmiedebergs Arch Pharmacol, 2006, 373(5): 376-380.
35.	霍秀青, 于忠和, 王萍. 低氧对肺动脉高压大鼠中介素合成和分泌的影响[J]. 中国全科医学, 2009, 12(10): 850-852.
36.	Pan CS, Yang JH, Cai DY, et al. Cardiovascular effects of newly discovered peptide intermedin/adrenomedullin 2[J]. Peptides, 2005, 26(9): 1640-1646.
37.	Fujisawa Y, Nagai Y, Miyatake A, et al. Effects of adrenomedullin 2 on regional hemodynamics in conscious rats[J]. Eur J Pharmacol, 2007, 558(1-3): 128-132.
38.	Kobayashi Y, Liu YJ, Gonda T, et al. Coronary vasodilatory response to a novel peptide, adrenomedullin 2[J]. Clin Exp Pharmacol Physiol, 2004, 31(Suppl 2): S49-S50.
39.	Cai Y, Xu MJ, Teng X, et al. Intermedin inhibits vascular calcification by increasing the level of matrix gamma-carboxyglutamic acid protein[J]. Cardiovasc Res, 2010, 85(4): 864-873.
40.	Szokodi I, Kinnunen P, Tavi P, et al. Evidence for cAMP-independent mechanisms mediating the effects of adrenomedullin, a new inotropic peptide[J]. Circulation, 1998, 97(11): 1062-1070.
41.	Yang JH, Qi YF, Jia YX, et al. Protective effects of intermedin/adrenomedullin 2 on ischemia/reperfusion injury in isolated rat hearts[J]. Peptides, 2005, 26(3): 501-507.
42.	杨淑娟, 李建强, 刘妮, 等. 中介素1-53对大鼠肺缺血再灌注损伤的保护作用[J]. 中国药物与临床, 2010, 10(2): 153-156.
43.	刘妮, 李建强, 杨淑娟, 等. 中介素1-53 对肺缺血再灌注损伤大鼠肺组织PPAR-γ表达的影响[J]. 中国现代医生, 2010, 48(4): 3-5.
44.	Fujisawa Y, Nagai Y, Miyatake A, et al. Roles of adrenomedullin 2 in regulating the cardiovascular and sympathetic nervous systems in conscious rats[J]. Am J Physiol Heart Circ Physiol, 2006, 290(3): 1120-1127.
45.	McDermott B, Zhao YY, McCoy F, et al. Upregulation of intermedin and reduced neutral endopeptidase expression in hypertensive cardiac hypertrophy[J]. J Mol Cell Cardiol, 2007, 42(6): S134.
46.	Bell D, McDermott BJ. Intermedin(adrenomedullin-2): a novel counter-regulatory peptide in the cardiovascular and renal systems[J]. Br J Pharmacol, 2008, 153(Suppl 1): 247-262.
47.	董劲, 陈晓平, 苏艳玲, 等. 肾血管性高血压大鼠肥厚心肌内中介素基因表达及缬沙坦、氨氯地平和依那普利的干预作用[J]. 生物医学工程学杂志, 2009, 26(5): 1082-1087.

1. 　Roh J, Chang CL, Bhalla A, et al. Intermedin is a calcitonin/CGRP family peptide acting through the calcitonin receptor-like receptor activity modifying protein receptor complexes[J]. J Biol Chem, 2004, 279(8): 7264-7274.
2. 　Takei Y, Inoue K, Ogoshi M, et al. Identification of novel adrenomedullin in mammals: a potent cardiovascular and renal regulator[J]. Febs Letters, 2004, 556(1-3): 53-58.
3. 　周芸, 李荣山. 中介素的生物学效应研究进展[J]. 医学综述, 2010, 16(1): 13-16.
4. 　Squire LR. Encyclopedia of Neuroscience[M]. Oxford: Academic Press, 2009: 509-552.
5. 　Yang JH, Jia YX, Pan CS, et al. Effects of intermedin1-53 on cardiac function and ischemia/reperfusion injury in isolated rat hearts[J]. Biochem Biophys Res Commun, 2005, 327(3): 713-719.
6. 　Ren YS, Yang JH, Zhang J, et al. Intermedin 1-53 in central nervous system elevates arterial blood pressure in rats[J]. Peptides, 2006, 27(1): 74-79.
7. 　Taylor MM, Bagley SL, Samson WK. Intermedin/adrenomedullin-2 acts within central nervous system to elevate blood pressure and inhibit food and water intake[J]. Am J Physiol Regul Integr Comp Physiol, 2005, 288(4): 919-927.
8. 　McLatchie LM, Fraser NJ, Main MJ, et al. RAMPs regulate the transport and ligand specifity of the calcitonin-receptor-liker receptor[J]. Nature, 1998, 393(6683): 332-339.
9. 　Dennis T, Fournier A, Cadieaux A, et al. hCGRP8-37: a CGRP antagonist revealing CGRP receptor heterogeneity in the brain and periphery[J]. J Pharmacol Exp Ther, 1990, 254(1): 123-128.
10. 　Poyner DR, Sexton PM, Marshall I, et al. IUPHAR XXXII. The mammalian calcitonin gene-related peptides, adrenomedullin, amylin, and calcitonin receptors[J]. Pharmacol Rev, 2002, 54(2): 233-246.
11. 　Hay DL, Howitt SG, Conner AC, et al. CL/RAMP2 and CL/RAMP3 produce pharmacologically distinct adrenomedullin receptors; a comparison of effects of adrenomedullin 22-52, CGRP8-37 and BIBN4096BS[J]. Br J Pharmacol, 2003, 140(3): 477-486.
12. 　Hay DL, Conner AC, Howitt SG, et al. The pharmacology of CGRP-responsive receptors in cultured and transfected cells[J]. Peptides, 2004, 25(11): 2019-2026.
13. 　Hay DL, Christopoulos G, Christopoulos A, et al. Pharmacological discrimination of calcitonin receptor: receptor activity modifying protein complexes[J]. Mol Pharmacol, 2005, 67(5): 1655-1665.
14. 　Morimoto R, Satoh F, Murakami O, et al. Expression of adrenomedullin 2/intermedin in human brain, heart, and kidney[J]. Peptides, 2007, 28(5): 1095-1103.
15. 　Totsune K, Takahashi K, Mackenzie HS, et al. Increased gene expression of adrenomedullin and adrenomedullin-receptor complexes, receptor-activity modifying protein(RAMP)2 and calcitonin-receptor-like receptor(CRLR) in the hearts of rats with congestive heart failure[J]. Clin Sci (Lond), 2000, 99(6):541-546.
16. 　Cueille C, Pidoux E, de Vernejoul MC, et al. Increased myocardial expression of RAMP1 and RAMP3 in rats with chronic heart failure[J]. Biochem Biophys Res Commun, 2002, 294(2): 340-346.
17. 　Zhao Y, Bell D, Smith LR, et al. Differential expression of components of the cardiomyocyte adrenomedullin/intermedin receptor system following blood pressure reduction in nitric oxide-deficient hypertension[J]. J Pharmacol Exp Ther, 2006, 316(3): 1269-1281.
18. 　Hagner S, Stahl U, Knoblauch B, et al. Calcitonin receptor-like receptor: identification and distribution in human peripheral tissues[J]. Cell Tissue Res, 2002, 310(1): 41-50.
19. 　Cottrell GS, Roosterman D, Marvizon JC, et al. Localization of calcitonin receptor-like receptor and receptor activity modifying protein 1 in enteric neurons, dorsal root ganglia, and the spinal cord of the rat[J]. J Comp Neurol, 2005, 490(3): 239-255.
20. 　Oliver KR, Wainwright A, Edvinsson L, et al. Immunohistochemical localization of calcitonin receptor-like receptor and receptor activity-modifying proteins in the human cerebral vasculature[J]. J Cereb Blood Flow Metab, 2002, 22(5): 620-629.
21. 　Autelitano DJ, Ridings R. Adrenomedullin signalling in cardiomyocytes is dependent upon CRLR and RAMP2 expression[J]. Peptides, 2001, 22(11): 1851-1857.
22. 　Nagae T, Mukoyama M, Sugawara A, et al. Rat receptor-activity-modifying proteins(RAMPs) for adrenomedullin/CGRP receptor: cloning and upregulation in obstructive nephropathy[J]. Biochem Biophys Res Commun, 2000, 270(1): 89-93.
23. 　Kamitani S, Asakawa M, Shimekake Y, et al. The RAMP2/CRLR complex is a functional adrenomedullin receptor in human endothelial and vascular smooth muscle cells[J]. FEBS Lett, 1999, 448(1): 111-114.
24. 　Christopoulos A, Christopoulos G, Morfis M, et al. Novel receptor partners and function of receptor activity-modifying proteins[J]. J Biol Chem, 2003, 278(5): 3293-3297.
25. 　Tfelt-Hansen J, Hansen JL, Smajilovic S, et al. Calcium receptor is functionally expressed in rat neonatal ventricular cardiomyocytes[J]. Am J Physiol, 2006, 290(3): 1165-1171.
26. 　Kuwasako K, Cao YN, Nagoshi Y, et al. Characterization of the human calcitonin gene-related peptide receptor subtypes associated with receptor activity-modifying proteins[J]. Mol Pharmacol, 2004, 65(1): 207-213.
27. 　Jia YX, Yang JH, Pan CS, et al. Intermedin1-53 protects the heart against isoproterenol-induced ischemic injury in rats[J]. Eur J Pharmacol, 2006, 549(1-3): 117-123.
28. 　Charles CJ, Rademaker MT, Richards AM. Hemodynamic, hormonal, and renal actions of adrenomedullin-2 in normal conscious sheep[J]. Endocrinology, 2006, 147(4): 1871-1877.
29. 　Dong F, Taylor MM, Samson WK, et al. Intermedin(adrenomedullin-2) enhances cardiac contractile function via a protein kinase C-and protein kinase A-dependent pathway in murine ventricular myocytes[J]. J Appl Physiol, 2006, 101(3): 778-784.
30. 　Yang JH, Pan CS, Jia YX, et al. Intermedin 1-53 activates l-arginine/nitric oxide synthase/nitric oxide pathway in rat aortas[J]. Biochem Biophys Res Commun, 2006, 341(2): 567-572.
31. 　Doganci S, Yildirim V, Bolcal C, et al. Intermedin(IMD/AM2) dilates the pig coronary vascular bed through release of nitric oxide[J]. Turkish J Thorac Cardiovasc Surg, 2011, 19(2): 242-246.
32. 　Kandilci HB, Gumusel B, Lippton H. Intermedin/adrenomedullin-2(IMD/AM2) relaxes rat pulmonary arterial rings in a nitric oxide and endothelial-dependent manner[J]. FASEB J, 2007, 21(4): 979.14.
33. 　Smith RS Jr, Gao L, Bledsoe G, et al. Intermedin is a new angiogenic growth factor[J]. Am J Physiol Heart Circ Physiol, 2009, 297(3): 1040-1047.
34. 　Abdelrahman AM, Pang CC. Effect of intermedin/adrenomedullin-2 on venous tone in conscious rats[J]. Naunyn Schmiedebergs Arch Pharmacol, 2006, 373(5): 376-380.
35. 　霍秀青, 于忠和, 王萍. 低氧对肺动脉高压大鼠中介素合成和分泌的影响[J]. 中国全科医学, 2009, 12(10): 850-852.
36. 　Pan CS, Yang JH, Cai DY, et al. Cardiovascular effects of newly discovered peptide intermedin/adrenomedullin 2[J]. Peptides, 2005, 26(9): 1640-1646.
37. 　Fujisawa Y, Nagai Y, Miyatake A, et al. Effects of adrenomedullin 2 on regional hemodynamics in conscious rats[J]. Eur J Pharmacol, 2007, 558(1-3): 128-132.
38. 　Kobayashi Y, Liu YJ, Gonda T, et al. Coronary vasodilatory response to a novel peptide, adrenomedullin 2[J]. Clin Exp Pharmacol Physiol, 2004, 31(Suppl 2): S49-S50.
39. 　Cai Y, Xu MJ, Teng X, et al. Intermedin inhibits vascular calcification by increasing the level of matrix gamma-carboxyglutamic acid protein[J]. Cardiovasc Res, 2010, 85(4): 864-873.
40. 　Szokodi I, Kinnunen P, Tavi P, et al. Evidence for cAMP-independent mechanisms mediating the effects of adrenomedullin, a new inotropic peptide[J]. Circulation, 1998, 97(11): 1062-1070.
41. 　Yang JH, Qi YF, Jia YX, et al. Protective effects of intermedin/adrenomedullin 2 on ischemia/reperfusion injury in isolated rat hearts[J]. Peptides, 2005, 26(3): 501-507.
42. 　杨淑娟, 李建强, 刘妮, 等. 中介素1-53对大鼠肺缺血再灌注损伤的保护作用[J]. 中国药物与临床, 2010, 10(2): 153-156.
43. 　刘妮, 李建强, 杨淑娟, 等. 中介素1-53 对肺缺血再灌注损伤大鼠肺组织PPAR-γ表达的影响[J]. 中国现代医生, 2010, 48(4): 3-5.
44. 　Fujisawa Y, Nagai Y, Miyatake A, et al. Roles of adrenomedullin 2 in regulating the cardiovascular and sympathetic nervous systems in conscious rats[J]. Am J Physiol Heart Circ Physiol, 2006, 290(3): 1120-1127.
45. 　McDermott B, Zhao YY, McCoy F, et al. Upregulation of intermedin and reduced neutral endopeptidase expression in hypertensive cardiac hypertrophy[J]. J Mol Cell Cardiol, 2007, 42(6): S134.
46. 　Bell D, McDermott BJ. Intermedin(adrenomedullin-2): a novel counter-regulatory peptide in the cardiovascular and renal systems[J]. Br J Pharmacol, 2008, 153(Suppl 1): 247-262.
47. 　董劲, 陈晓平, 苏艳玲, 等. 肾血管性高血压大鼠肥厚心肌内中介素基因表达及缬沙坦、氨氯地平和依那普利的干预作用[J]. 生物医学工程学杂志, 2009, 26(5): 1082-1087.

West China Medical Journal

中介素在心血管系统的研究进展

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