Role of secretory protein GREM1 in systemic-to-pulmonary shunt associated pulmonary arterial hypertension_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

LIU Xu ^1,2 , DENG Hongyu ² ,  ZHOU Ping ¹

1. Department of Ultrasound Diagnosis of The Third Xiangya Hospital of Central South University, Changsha, 410013, P.R.China;
2. Department of Ultrasound of Hunan Cancer Hospital, Changsha, 410013, P.R.China;

Corresponding author：

ZHOU Ping, Email: zhouping1000@hotmail.com

Keywords：

Congenital heart disease; systemic-to-pulmonary shunt; pulmonary arterial hypertension; pulmonary vascular remodeling; bone morphogenetic protein antagonist

DOI：

10.7507/1007-4848.202007070

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Objective To explore the possibility that GREM1, a bone morphogenetic protein (BMP) antagonist, is a mechanical explanation for BMP signal suppression in congenital heart disease associated pulmonary arterial hypertension (CHD/PAH) patients.Methods Systemic-to-pulmonary shunt induced PAH was surgically established in rats. At the postoperative 12^th week, right heart catheterization and echocardiography evaluation were performed to evaluate hemodynamic indexes and morphology of right heart system. Right heart hypotrophy index and pulmonary vascular remodeling were evaluated. Changes of BMP signal pathway related proteins and GREM1 in lungs and plasma GREM1 concentration were detected. The effect of GREM1 on the proliferation and apoptosis of pulmonary arterial endothelial cells (PAECs) was also explored.Results The hypertensive status was successfully reproduced in rats with systemic-to-pulmonary shunt model. BMP signal pathway was suppressed but GREM1 was up-regulated with no change in hypoxia inducible factor-1 in lungs exposed to systemic-to-pulmonary shunt, while this trend was reversed by systemic-to-pulmonary shunt correction (P<0.05). Immunohistochemical staining demonstrated enhanced staining of GREM1 in remodeled pulmonary arteries. In vitro experiments found that BMP signal was down-regulated but GREM1 expression and secretion were up-regulated in proliferative PAECs (P<0.05). Furthermore, BMP2 significantly inhibited PAECs proliferation and promoted PAECs apoptosis (P<0.05), which could be antagonized by GREM1. In addition, plasma level of GREM1 in rats with systemic-to-pulmonary shunt was also increased and positively correlated with pulmonary hemodynamic indexes.Conclusion Systemic-to-pulmonary shunt induces the up-regulation of GREM1 in lungs, which promotes pulmonary vascular remodeling via antagonizing BMP cascade. These results present a new mechanical explanation for BMP pathway suppression in lungs of CHD/PAH patients.

Citation： LIU Xu, DENG Hongyu, ZHOU Ping. Role of secretory protein GREM1 in systemic-to-pulmonary shunt associated pulmonary arterial hypertension. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2021, 28(4): 479-487. doi: 10.7507/1007-4848.202007070 Copy

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2.	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.
3.	Thomson JR, Machado RD, Pauciulo MW, et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J Med Genet, 2000, 37(10): 741-745.
4.	Du L, Sullivan CC, Chu D, et al. Signaling molecules in nonfamilial pulmonary hypertension. N Engl J Med, 2003, 348(6): 500-509.
5.	Meng L, Liu X, Teng X, et al. DAN plays important compensatory roles in systemic-to-pulmonary shunt associated pulmonary arterial hypertension. Acta Physiol (Oxf), 2019, 226(3): e13263.
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7.	Cahill E, Costello CM, Rowan SC, et al. Gremlin plays a key role in the pathogenesis of pulmonary hypertension. Circulation, 2012, 125(7): 920-930.
8.	Meng LK, Liu XY, Zheng Z, et al. Original rat model of high kinetic unilateral pulmonary hypertension surgically induced by combined surger. J Thorac Cardiovasc Surg, 2013, 146(5): 1220-1226.
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14.	Oudiz RJ, Brundage BH, Galiè N, et al. Tadalafil for the treatment of pulmonary arterial hypertension: a double-blind 52-week uncontrolled extension study. J Am Coll Cardiol, 2012, 60(8): 768-774.
15.	Gatzoulis MA, Landzberg M, Beghetti M, et al. Evaluation of macitentan in patients with eisenmenger syndrome. Circulation, 2019, 139(1): 51-63.
16.	Lajoie AC, Lauzière G, Lega JC, et al. Combination therapy versus monotherapy for pulmonary arterial hypertension: A meta-analysis. Lancet Respir Med, 2016, 4(4): 291-305.
17.	Archer S, Rich S. Primary pulmonary hypertension: a vascular biology and translational research "Work in progress". Circulation, 2000, 102(22): 2781-2791.
18.	Heath D, Edwards JE. The pathology of hypertensive pulmonary vascular disease; a description of six grades of structural changes in the pulmonary arteries with special reference to congenital cardiac septal defects. Circulation, 1958, 18(4 Part 1): 533-547.
19.	Provencher S, Archer SL, Ramirez FD, et al. Standards and methodological rigor in pulmonary arterial hypertension preclinical and translational research. Circ Res, 2018, 122(7): 1021-1032.
20.	Lévy M, Maurey C, Celermajer DS, et al. Impaired apoptosis of pulmonary endothelial cells is associated with intimal proliferation and irreversibility of pulmonary hypertension in congenital heart disease. J Am Coll Cardiol, 2007, 49(7): 803-810.
21.	Li G, Zhang H, Zhao L, et al. The expression of survivin in irreversible pulmonary arterial hypertension rats and its value in evaluating the reversibility of pulmonary arterial hypertension secondary to congenital heart disease. Pulm Circ, 2019, 9(3): 1-11.
22.	McMurtry MS, Archer SL, Altieri DC, et al. Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension. J Clin Invest, 2005, 115(6): 1479-1491.
23.	Nasim MT, Ogo T, Chowdhury HM, et al. BMPR-Ⅱ deficiency elicits pro-proliferative and anti-apoptotic responses through the activation of TGFβ-TAK1-MAPK pathways in PAH. Hum Mol Genet, 2012, 21(11): 2548-2558.
24.	Limsuwan A, Choubtum L, Wattanasirichaigoon D. 5′UTR repeat polymorphisms of the BMPR2 gene in children with pulmonary hypertension associated with congenital heart disease. Heart Lung Circ, 2013, 22(3): 204-210.
25.	Roberts KE, McElroy JJ, Wong WP, et al. BMPR2 mutations in pulmonary arterial hypertension with congenital heart disease. Eur Respir J, 2004, 24(3): 371-374.
26.	Costello CM, Howell K, Cahill E, et al. Lung-selective gene responses to alveolar hypoxia: potential role for the bone morphogenetic antagonist gremlin in pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol, 2008, 295(2): L272-L284.
27.	Chakraborty AA, Laukka T, Myllykoski M, et al. Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate. Science, 2019, 363(6432): 1217-1222.

1. Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol, 2013, 62(25 Suppl): D34-D41.
2. 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.
3. Thomson JR, Machado RD, Pauciulo MW, et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J Med Genet, 2000, 37(10): 741-745.
4. Du L, Sullivan CC, Chu D, et al. Signaling molecules in nonfamilial pulmonary hypertension. N Engl J Med, 2003, 348(6): 500-509.
5. Meng L, Liu X, Teng X, et al. DAN plays important compensatory roles in systemic-to-pulmonary shunt associated pulmonary arterial hypertension. Acta Physiol (Oxf), 2019, 226(3): e13263.
6. Xu W, Erzurum SC. Endothelial cell energy metabolism, proliferation, and apoptosis in pulmonary hypertension. Compr Physiol, 2011, 1(1): 357-372.
7. Cahill E, Costello CM, Rowan SC, et al. Gremlin plays a key role in the pathogenesis of pulmonary hypertension. Circulation, 2012, 125(7): 920-930.
8. Meng LK, Liu XY, Zheng Z, et al. Original rat model of high kinetic unilateral pulmonary hypertension surgically induced by combined surger. J Thorac Cardiovasc Surg, 2013, 146(5): 1220-1226.
9. 陈寄梅, 李守军. 先天性心脏病外科治疗中国专家共识(六). 中国胸心血管外科临床杂志, 2020, 27(7): 725-729.
10. Heath D, Edwards JE. The pathology of hypertensive pulmonary vascular disease: A description of six grades of structural changes in the pulmonary arteries with special reference to congenital cardiac septal defects. Circulation, 1958, 18(4 Part 1): 533-547.
11. Zhang R, Dai LZ, Xie WP, et al. Survival of Chinese patients with pulmonary arterial hypertension in the modern treatment era. Chest, 2011, 140(2): 301-309.
12. van Dissel AC, Mulder BJ, Bouma BJ. The changing landscape of pulmonary arterial hypertension in the adult with congenital heart disease. J Clin Med, 2017, 6(4): 40.
13. Beghetti M, Channick RN, Chin KM, et al. Selexipag treatment for pulmonary arterial hypertension associated with congenital heart disease after defect correction: insights from the randomised controlled GRIPHON study. Eur J Heart Fail, 2019, 21(3): 352-359.
14. Oudiz RJ, Brundage BH, Galiè N, et al. Tadalafil for the treatment of pulmonary arterial hypertension: a double-blind 52-week uncontrolled extension study. J Am Coll Cardiol, 2012, 60(8): 768-774.
15. Gatzoulis MA, Landzberg M, Beghetti M, et al. Evaluation of macitentan in patients with eisenmenger syndrome. Circulation, 2019, 139(1): 51-63.
16. Lajoie AC, Lauzière G, Lega JC, et al. Combination therapy versus monotherapy for pulmonary arterial hypertension: A meta-analysis. Lancet Respir Med, 2016, 4(4): 291-305.
17. Archer S, Rich S. Primary pulmonary hypertension: a vascular biology and translational research "Work in progress". Circulation, 2000, 102(22): 2781-2791.
18. Heath D, Edwards JE. The pathology of hypertensive pulmonary vascular disease; a description of six grades of structural changes in the pulmonary arteries with special reference to congenital cardiac septal defects. Circulation, 1958, 18(4 Part 1): 533-547.
19. Provencher S, Archer SL, Ramirez FD, et al. Standards and methodological rigor in pulmonary arterial hypertension preclinical and translational research. Circ Res, 2018, 122(7): 1021-1032.
20. Lévy M, Maurey C, Celermajer DS, et al. Impaired apoptosis of pulmonary endothelial cells is associated with intimal proliferation and irreversibility of pulmonary hypertension in congenital heart disease. J Am Coll Cardiol, 2007, 49(7): 803-810.
21. Li G, Zhang H, Zhao L, et al. The expression of survivin in irreversible pulmonary arterial hypertension rats and its value in evaluating the reversibility of pulmonary arterial hypertension secondary to congenital heart disease. Pulm Circ, 2019, 9(3): 1-11.
22. McMurtry MS, Archer SL, Altieri DC, et al. Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension. J Clin Invest, 2005, 115(6): 1479-1491.
23. Nasim MT, Ogo T, Chowdhury HM, et al. BMPR-Ⅱ deficiency elicits pro-proliferative and anti-apoptotic responses through the activation of TGFβ-TAK1-MAPK pathways in PAH. Hum Mol Genet, 2012, 21(11): 2548-2558.
24. Limsuwan A, Choubtum L, Wattanasirichaigoon D. 5′UTR repeat polymorphisms of the BMPR2 gene in children with pulmonary hypertension associated with congenital heart disease. Heart Lung Circ, 2013, 22(3): 204-210.
25. Roberts KE, McElroy JJ, Wong WP, et al. BMPR2 mutations in pulmonary arterial hypertension with congenital heart disease. Eur Respir J, 2004, 24(3): 371-374.
26. Costello CM, Howell K, Cahill E, et al. Lung-selective gene responses to alveolar hypoxia: potential role for the bone morphogenetic antagonist gremlin in pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol, 2008, 295(2): L272-L284.
27. Chakraborty AA, Laukka T, Myllykoski M, et al. Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate. Science, 2019, 363(6432): 1217-1222.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Role of secretory protein GREM1 in systemic-to-pulmonary shunt associated pulmonary arterial hypertension

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