Research progress of bone morphogenetic protein-4 in pulmonary vascular remodeling in patients with pulmonary hypertension_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

QIAN Hong ,  HU Jia

Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, 610041, P.R.China;

Corresponding author：

HU Jia, Email: humanjia@msn.com

Keywords：

Pulmonary hypertension; bone morphogenetic protein; pulmonary vascular remodeling

DOI：

10.7507/1007-4848.201805064

Video：

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Pulmonary hypertension is a disease characterized by pulmonary artery pressure increased, with or without small artery pathological change, which ultimately leads to right heart failure or even death. Pulmonary hypertension seriously threatens to human health, however, the pathogenesis of pulmonary hypertension is unclear. Previous studies have found that bone morphogenetic protein (BMP) signaling system played an important role in the progress of pulmonary hypertension. In the current review, we describe the mechanism of BMP4 in the development of pulmonary hypertension.

Citation： QIAN Hong, HU Jia. Research progress of bone morphogenetic protein-4 in pulmonary vascular remodeling in patients with pulmonary hypertension. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2019, 26(3): 274-277. doi: 10.7507/1007-4848.201805064 Copy

1.	Rubin LJ. Primary pulmonary hypertension. N Engl J Med, 1997, 336(2): 111-117.
2.	Humbert M, Khaltaev N, Bousquet J, et al. Pulmonary hypertension: from an orphan disease to a public health problem. Chest, 2007, 132(2): 365-367.
3.	Galie` N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J, 2015, 46(4): 903-975.
4.	Anderson L, Lowery JW, Frank DB, et al. Bmp2 and Bmp4 exert opposing effects in hypoxic pulmonary hypertension. Am J Physiol Regul Integr Comp Physiol, 2010, 298(3): R833-R842.
5.	Urist MR. Bone: formation by autoinduction. Science, 1965, 150(3698): 893-899.
6.	Ducy P, Schinke T, Karsenty G. The osteoblast: a sophisticated fibroblast under central surveillance. Science, 2000, 289(5484): 1501-1504.
7.	Wong WT, Tian XY, Huang Y. Endothelial dysfunction in diabetes and hypertension: cross talk in RAS, BMP4, and ROS-dependent COX-2-derived prostanoids. J Cardiovasc Pharmacol, 2013, 61(3): 204-214.
8.	Cai J, Pardali E, Sánchez-Duffhues G, et al. BMP signaling in vascular diseases. FEBS Lett, 2012, 586(14): 1993-2002.
9.	Pachori AS, Custer L, Hansen D, et al. Bone morphogenetic protein 4 mediates myocardial ischemic injury through JNK-dependent signaling pathway. J Mol Cell Cardiol, 2010, 48(6): 1255-1265.
10.	Eickelberg O, Morty RE. Transforming growth factor beta/bone morphogenic protein signaling in pulmonary arterial hypertension: remodeling revisited. Trends Cardiovasc Med, 2007, 17(8): 263-269.
11.	Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature, 2003, 425(6958): 577-584.
12.	Miyazono K, Maeda S, Imamura T. BMP receptor signaling: transcriptional targets, regulation of signals, and signaling cross-talk. Cytokine Growth Factor Rev, 2005, 16(3): 251-263.
13.	Chan SY, Loscalzo J. Pathogenic mechanisms of pulmonary arterial hypertension. J Mol Cell Cardiol, 2008, 44(1): 14-30.
14.	Archer S, Rich S. Primary pulmonary hypertension: a vascular biology and translational research " Work in progress”. Circulation, 2000, 102(22): 2781-2791.
15.	Newman JH, Phillips JA 3rd, Loyd JE. Narrative review: the enigma of pulmonary arterial hypertension: new insights from genetic studies. Ann Intern Med, 2008, 148(4): 278-283.
16.	Cogan JD, Pauciulo MW, Batchman AP, et al. High frequency of BMPR2 exonic deletions/duplications in familial pulmonary arterial hypertension. Am J Respir Crit Care Med, 2006, 174(5): 590-598.
17.	Machado RD, Pauciulo MW, Thomson JR, et al. BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. Am J Hum Genet, 2001, 68(1): 92-102.
18.	Davies RJ, Morrell NW. Molecular mechanisms of pulmonary arterial hypertension: role of mutations in the bone morphogenetic protein type Ⅱ receptor. Chest, 2008, 134(6): 1271-1277.
19.	Zhang Y, Wang Y, Yang K, et al. BMP4 increases the expression of TRPC and basal. PLoS One, 2014, 9(12): e112695.
20.	Teichert-Kuliszewska K, Kutryk MJ, Kuliszewski MA, et al. Bone morphogenetic protein receptor-2 signaling promotes pulmonary arterial endothelial cell survival: implications for loss-of-function mutations in the pathogenesis of pulmonary hypertension. Circ Res, 2006, 98(2): 209-217.
21.	Morrell NW, Adnot S, Archer SL, et al. Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol, 2009, 54(1 Suppl): S20-S31.
22.	Frank DB, Abtahi A, Yamaguchi DJ, et al. Bone morphogenetic protein 4 promotes pulmonary vascular remodeling in hypoxic pulmonary hypertension. Circ Res, 2005, 97(5): 496-504.
23.	Long L, MacLean MR, Jeffery TK, et al. Serotonin increases susceptibility to pulmonary hypertension in BMPR2-deficient mice. Circ Res, 2006, 98(6): 818-827.
24.	Frank DB, Lowery J, Anderson L, et al. Increased susceptibility to hypoxic pulmonary hypertension in Bmpr2 mutant mice is associated with endothelial dysfunction in the pulmonary vasculature. Am J Physiol Lung Cell Mol Physiol, 2008, 294(1): L98-L109.
25.	Yang X, Long L, Southwood M, et al. Dysfunctional Smad signaling contributes to abnormal smooth muscle cell proliferation in familial pulmonary arterial hypertension. Circ Res, 2005, 96(10): 1053-1063.
26.	Gerasimovskaya EV, Tucker DA, Stenmark KR. Activation of phosphatidylinositol 3-kinase, Akt, and mammalian target of rapamycin is necessary for hypoxia-induced pulmonary artery adventitial fibroblast proliferation. J Appl Physiol, 1985, 2005, 98(2): 722-731.
27.	Downward J. Mechanisms and consequences of activation of protein kinase B/Akt. Curr Opin Cell Biol, 1998, 10(2): 262-267.
28.	Wu J, Yu Z, Su D. BMP4 protects rat pulmonary arterial smooth muscle cells from apoptosis by PI3K/AKT/Smad1/5/8 signaling. Int J Mol Sci, 2014, 15(8): 13738-13754.
29.	Porter AG, Jänicke RU. Emerging roles of caspase-3 in apoptosis. Cell Death Differ, 1999, 6(2): 99-104.
30.	Cook SA, Sugden PH, Clerk A. Regulation of bcl-2 family proteins during development and in response to oxidative stress in cardiac myocytes: association with changes in mitochondrial membrane potential. Circ Res, 1999, 85(10): 940-949.
31.	McDaniel SS, Platoshyn O, Wang J, et al. Capacitative Ca(2+) entry in agonist-induced pulmonary vasoconstriction. Am J Physiol Lung Cell Mol Physiol, 2001, 280(5): L870-L880.
32.	Harper JF, Harmon A. Plants, symbiosis and parasites: a calcium signalling connection. Nat Rev Mol Cell Biol, 2005, 6(7): 555-566.
33.	Wang J, Shimoda LA, Sylvester JT. Capacitative calcium entry and TRPC channel proteins are expressed in rat distal pulmonary arterial smooth muscle. Am J Physiol Lung Cell Mol Physiol, 2004, 286(4): L848-L858.
34.	Lu W, Ran P, Zhang D, et al. Sildenafil inhibits chronically hypoxic upregulation of canonical transient receptor potential expression in rat pulmonary arterial smooth muscle. Am J Physiol Cell Physiol, 2010, 298(1): C114-C123.
35.	Lu W, Ran P, Zhang D, et al. Bone morphogenetic protein 4 enhances canonical transient receptor potential expression, store-operated Ca2+ entry, and basal. Am J Physiol Cell Physiol, 2010, 299(6): C1370-1378.
36.	Yang K, Lu W, Jia J, et al. Noggin inhibits hypoxia-induced proliferation by targeting store-operated calcium entry and transient receptor potential cation channels. Am J Physiol Cell Physiol, 2015, 308(11): 869-878.
37.	张会, 浦奎, 李静梅, 等. 肺动脉高压再认识. 中国慢性病预防与控制, 2015, 23(8): 637-639.
38.	胡选义, 陈黔苏, 吴观生, 等. 西地那非治疗先天性心脏病伴肺动脉高压术后儿童的疗效和安全性观察. 四川大学学报 (医学版), 2011, 42(6): 887-888.
39.	Austin ED, Loyd JE. The genetics of pulmonary arterial hypertension. Circ Res, 2014, 115(1): 189-202.
40.	Boucherat O, Bonnet S. NOGGIN: a new therapeutic target for PH? Focus on "Noggin inhibits hypoxia-induced proliferation by targeting store-operated calcium entry and transient receptor potential cation channels". Am J Physiol Cell Physiol, 2015, 308(11): C867-C868.

1. Rubin LJ. Primary pulmonary hypertension. N Engl J Med, 1997, 336(2): 111-117.
2. Humbert M, Khaltaev N, Bousquet J, et al. Pulmonary hypertension: from an orphan disease to a public health problem. Chest, 2007, 132(2): 365-367.
3. Galie` N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J, 2015, 46(4): 903-975.
4. Anderson L, Lowery JW, Frank DB, et al. Bmp2 and Bmp4 exert opposing effects in hypoxic pulmonary hypertension. Am J Physiol Regul Integr Comp Physiol, 2010, 298(3): R833-R842.
5. Urist MR. Bone: formation by autoinduction. Science, 1965, 150(3698): 893-899.
6. Ducy P, Schinke T, Karsenty G. The osteoblast: a sophisticated fibroblast under central surveillance. Science, 2000, 289(5484): 1501-1504.
7. Wong WT, Tian XY, Huang Y. Endothelial dysfunction in diabetes and hypertension: cross talk in RAS, BMP4, and ROS-dependent COX-2-derived prostanoids. J Cardiovasc Pharmacol, 2013, 61(3): 204-214.
8. Cai J, Pardali E, Sánchez-Duffhues G, et al. BMP signaling in vascular diseases. FEBS Lett, 2012, 586(14): 1993-2002.
9. Pachori AS, Custer L, Hansen D, et al. Bone morphogenetic protein 4 mediates myocardial ischemic injury through JNK-dependent signaling pathway. J Mol Cell Cardiol, 2010, 48(6): 1255-1265.
10. Eickelberg O, Morty RE. Transforming growth factor beta/bone morphogenic protein signaling in pulmonary arterial hypertension: remodeling revisited. Trends Cardiovasc Med, 2007, 17(8): 263-269.
11. Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature, 2003, 425(6958): 577-584.
12. Miyazono K, Maeda S, Imamura T. BMP receptor signaling: transcriptional targets, regulation of signals, and signaling cross-talk. Cytokine Growth Factor Rev, 2005, 16(3): 251-263.
13. Chan SY, Loscalzo J. Pathogenic mechanisms of pulmonary arterial hypertension. J Mol Cell Cardiol, 2008, 44(1): 14-30.
14. Archer S, Rich S. Primary pulmonary hypertension: a vascular biology and translational research " Work in progress”. Circulation, 2000, 102(22): 2781-2791.
15. Newman JH, Phillips JA 3rd, Loyd JE. Narrative review: the enigma of pulmonary arterial hypertension: new insights from genetic studies. Ann Intern Med, 2008, 148(4): 278-283.
16. Cogan JD, Pauciulo MW, Batchman AP, et al. High frequency of BMPR2 exonic deletions/duplications in familial pulmonary arterial hypertension. Am J Respir Crit Care Med, 2006, 174(5): 590-598.
17. Machado RD, Pauciulo MW, Thomson JR, et al. BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. Am J Hum Genet, 2001, 68(1): 92-102.
18. Davies RJ, Morrell NW. Molecular mechanisms of pulmonary arterial hypertension: role of mutations in the bone morphogenetic protein type Ⅱ receptor. Chest, 2008, 134(6): 1271-1277.
19. Zhang Y, Wang Y, Yang K, et al. BMP4 increases the expression of TRPC and basal. PLoS One, 2014, 9(12): e112695.
20. Teichert-Kuliszewska K, Kutryk MJ, Kuliszewski MA, et al. Bone morphogenetic protein receptor-2 signaling promotes pulmonary arterial endothelial cell survival: implications for loss-of-function mutations in the pathogenesis of pulmonary hypertension. Circ Res, 2006, 98(2): 209-217.
21. Morrell NW, Adnot S, Archer SL, et al. Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol, 2009, 54(1 Suppl): S20-S31.
22. Frank DB, Abtahi A, Yamaguchi DJ, et al. Bone morphogenetic protein 4 promotes pulmonary vascular remodeling in hypoxic pulmonary hypertension. Circ Res, 2005, 97(5): 496-504.
23. Long L, MacLean MR, Jeffery TK, et al. Serotonin increases susceptibility to pulmonary hypertension in BMPR2-deficient mice. Circ Res, 2006, 98(6): 818-827.
24. Frank DB, Lowery J, Anderson L, et al. Increased susceptibility to hypoxic pulmonary hypertension in Bmpr2 mutant mice is associated with endothelial dysfunction in the pulmonary vasculature. Am J Physiol Lung Cell Mol Physiol, 2008, 294(1): L98-L109.
25. Yang X, Long L, Southwood M, et al. Dysfunctional Smad signaling contributes to abnormal smooth muscle cell proliferation in familial pulmonary arterial hypertension. Circ Res, 2005, 96(10): 1053-1063.
26. Gerasimovskaya EV, Tucker DA, Stenmark KR. Activation of phosphatidylinositol 3-kinase, Akt, and mammalian target of rapamycin is necessary for hypoxia-induced pulmonary artery adventitial fibroblast proliferation. J Appl Physiol, 1985, 2005, 98(2): 722-731.
27. Downward J. Mechanisms and consequences of activation of protein kinase B/Akt. Curr Opin Cell Biol, 1998, 10(2): 262-267.
28. Wu J, Yu Z, Su D. BMP4 protects rat pulmonary arterial smooth muscle cells from apoptosis by PI3K/AKT/Smad1/5/8 signaling. Int J Mol Sci, 2014, 15(8): 13738-13754.
29. Porter AG, Jänicke RU. Emerging roles of caspase-3 in apoptosis. Cell Death Differ, 1999, 6(2): 99-104.
30. Cook SA, Sugden PH, Clerk A. Regulation of bcl-2 family proteins during development and in response to oxidative stress in cardiac myocytes: association with changes in mitochondrial membrane potential. Circ Res, 1999, 85(10): 940-949.
31. McDaniel SS, Platoshyn O, Wang J, et al. Capacitative Ca(2+) entry in agonist-induced pulmonary vasoconstriction. Am J Physiol Lung Cell Mol Physiol, 2001, 280(5): L870-L880.
32. Harper JF, Harmon A. Plants, symbiosis and parasites: a calcium signalling connection. Nat Rev Mol Cell Biol, 2005, 6(7): 555-566.
33. Wang J, Shimoda LA, Sylvester JT. Capacitative calcium entry and TRPC channel proteins are expressed in rat distal pulmonary arterial smooth muscle. Am J Physiol Lung Cell Mol Physiol, 2004, 286(4): L848-L858.
34. Lu W, Ran P, Zhang D, et al. Sildenafil inhibits chronically hypoxic upregulation of canonical transient receptor potential expression in rat pulmonary arterial smooth muscle. Am J Physiol Cell Physiol, 2010, 298(1): C114-C123.
35. Lu W, Ran P, Zhang D, et al. Bone morphogenetic protein 4 enhances canonical transient receptor potential expression, store-operated Ca2+ entry, and basal. Am J Physiol Cell Physiol, 2010, 299(6): C1370-1378.
36. Yang K, Lu W, Jia J, et al. Noggin inhibits hypoxia-induced proliferation by targeting store-operated calcium entry and transient receptor potential cation channels. Am J Physiol Cell Physiol, 2015, 308(11): 869-878.
37. 张会, 浦奎, 李静梅, 等. 肺动脉高压再认识. 中国慢性病预防与控制, 2015, 23(8): 637-639.
38. 胡选义, 陈黔苏, 吴观生, 等. 西地那非治疗先天性心脏病伴肺动脉高压术后儿童的疗效和安全性观察. 四川大学学报 (医学版), 2011, 42(6): 887-888.
39. Austin ED, Loyd JE. The genetics of pulmonary arterial hypertension. Circ Res, 2014, 115(1): 189-202.
40. Boucherat O, Bonnet S. NOGGIN: a new therapeutic target for PH? Focus on "Noggin inhibits hypoxia-induced proliferation by targeting store-operated calcium entry and transient receptor potential cation channels". Am J Physiol Cell Physiol, 2015, 308(11): C867-C868.

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