Internal relationship between Hippo pathway and pulmonary hypertension_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

SONG Zhiruo ^1,2 ,  QIAN Hong ¹

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

Corresponding author：

QIAN Hong, Email: qianhong2222@126.com

Keywords：

Pulmonary hypertension; Hippo pathway; pulmonary vascular remodeling; review

DOI：

10.7507/1007-4848.202011001

Video：

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Pulmonary hypertension is a kind of progressive pulmonary vascular diseases in which there is excessive vasoconstriction and abnormal pulmonary vascular remodeling, and then a gradual increase in pulmonary arterial pressure, and it eventually leads to right ventricular failure and even death. The pathogenesis of pulmonary hypertension is still uncertain, but some studies suggest that Hippo pathway or some components of the Hippo pathway may be involved in the progress of pulmonary hypertension. In this review, we describe the mechanism of the Hippo pathway or some components of the Hippo pathway in the progress of pulmonary hypertension.

Citation： SONG Zhiruo, QIAN Hong. Internal relationship between Hippo pathway and pulmonary hypertension. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2021, 28(11): 1376-1380. doi: 10.7507/1007-4848.202011001 Copy

1.	Oliveira AC, Richards EM, Raizada MK. Pulmonary hypertension: Pathophysiology beyond the lung. Pharmacol Res, 2020, 151: 104518.
2.	中华医学会心血管病学分会肺血管病学组, 中华心血管病杂志编辑委员会. 中国肺高血压诊断和治疗指南 2018. 中华心血管病杂志, 2018, 46(12): 933-964.
3.	Rosenkranz S. Pulmonary hypertension 2015: Current definitions, terminology, and novel treatment options. Clin Res Cardiol, 2015, 104(3): 197-207.
4.	McClenaghan C, Woo KV, Nichols CG. Pulmonary hypertension and ATP-sensitive potassium channels. Hypertension, 2019, 74(1): 14-22.
5.	Hong AW, Meng Z, Guan KL. The Hippo pathway in intestinal regeneration and disease. Nat Rev Gastroenterol Hepatol, 2016, 13(6): 324-337.
6.	Calses PC, Crawford JJ, Lill JR, et al. Hippo pathway in cancer: Aberrant regulation and therapeutic opportunities. Trends Cancer, 2019, 5(5): 297-307.
7.	Karaman R, Halder G. Cell junctions in Hippo signaling. Cold Spring Harb Perspect Biol, 2018, 10(5): a028753.
8.	Wang J, Liu S, Heallen T, et al. The Hippo pathway in the heart: Pivotal roles in development, disease, and regeneration. Nat Rev Cardiol, 2018, 15(11): 672-684.
9.	Wang W, Xiao ZD, Li X, et al. AMPK modulates Hippo pathway activity to regulate energy homeostasis. Nat Cell Biol, 2015, 17(4): 490-499.
10.	Meng Z, Moroishi T, Guan KL. Mechanisms of Hippo pathway regulation. Genes Dev, 2016, 30(1): 1-17.
11.	White SM, Murakami S, Yi C. The complex entanglement of Hippo-Yap/Taz signaling in tumor immunity. Oncogene, 2019, 38(16): 2899-2909.
12.	Misra JR, Irvine KD. The Hippo signaling network and its biological functions. Annu Rev Genet, 2018, 52: 65-87.
13.	Xu W, Yang Z, Xie C, et al. PTEN lipid phosphatase inactivation links the Hippo and PI3K/Akt pathways to induce gastric tumorigenesis. J Exp Clin Cancer Res, 2018, 37(1): 198.
14.	Yu FX, Zhao B, Guan KL. Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell, 2015, 163(4): 811-828.
15.	Galiè 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 Heart J, 2016, 37(1): 67-119.
16.	Kondo T, Okumura N, Adachi S, et al. Pulmonary hypertension: Diagnosis, management, and treatment. Nagoya J Med Sci, 2019, 81(1): 19-30.
17.	Kim D, George MP. Pulmonary hypertension. Med Clin North Am, 2019, 103(3): 413-423.
18.	钱宏, 郭应强. 左心疾病相关性肺动脉高压的研究现状. 中国胸心血管外科临床杂志, 2019, 26(4): 394-403.
19.	Lücke E, Schmeißer A, Schreiber J. Pulmonary hypertension: Diagnostics, classification and therapy. Anasthesiol Intensivmed Notfallmed Schmerzther, 2019, 54(5): 320-333.
20.	Dasgupta A, Wu D, Tian L, et al. Mitochondria in the pulmonary vasculature in health and disease: Oxygen-sensing, metabolism, and dynamics. Compr Physiol, 2020, 10(2): 713-765.
21.	Dupont S, Morsut L, Aragona M, et al. Role of YAP/TAZ in mechanotransduction. Nature, 2011, 474(7350): 179-183.
22.	He J, Bao Q, Yan M, et al. The role of Hippo/YES-associated protein signalling in vascular remodelling associated with cardiovascular disease. Br J Pharmacol, 2018, 175(8): 1354-1361.
23.	Aragona M, Panciera T, Manfrin A, et al. A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors. Cell, 2013, 154(5): 1047-1059.
24.	Wu D, Birukov K. Endothelial cell mechano-metabolomic coupling to disease states in the lung microvasculature. Front Bioeng Biotechnol, 2019, 7: 172.
25.	Bertero T, Cottrill KA, Lu Y, et al. Matrix remodeling promotes pulmonary hypertension through feedback mechanoactivation of the YAP/TAZ-miR-130/301 circuit. Cell Rep, 2015, 13(5): 1016-1032.
26.	Xie H, Wu L, Deng Z, et al. Emerging roles of YAP/TAZ in lung physiology and diseases. Life Sci, 2018, 214: 176-183.
27.	Thenappan T, Chan SY, Weir EK. Role of extracellular matrix in the pathogenesis of pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol, 2018, 315(5): H1322-H1331.
28.	钱宏, 胡佳. 骨形成蛋白-4 对于肺动脉高压患者肺血管重构作用的研究进展. 中国胸心血管外科临床杂志, 2019, 26(3): 274-277.
29.	Dieffenbach PB, Maracle M, Tschumperlin DJ, et al. Mechanobiological feedback in pulmonary vascular disease. Front Physiol, 2018, 9: 951.
30.	Dieffenbach PB, Haeger CM, Coronata AMF, et al. Arterial stiffness induces remodeling phenotypes in pulmonary artery smooth muscle cells via YAP/TAZ-mediated repression of cyclooxygenase-2. Am J Physiol Lung Cell Mol Physiol, 2017, 313(3): L628-L647.
31.	Ahmed A, Ahmed S, Arvidsson M, et al. Elevated plasma sRAGE and IGFBP7 in heart failure decrease after heart transplantation in association with haemodynamics. ESC Heart Fail, 2020, 7(5): 2340-2353.
32.	Bertero T, Oldham WM, Cottrill KA, et al. Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension. J Clin Invest, 2016, 126(9): 3313-3335.
33.	Ardestani A, Lupse B, Maedler K. Hippo signaling: Key emerging pathway in cellular and whole-body metabolism. Trends Endocrinol Metab, 2018, 29(7): 492-509.
34.	Shi XF, Su YC. Vascular metabolic mechanisms of pulmonary hypertension. Curr Med Sci, 2020, 40(3): 444-454.
35.	Boucherat O, Bonnet S, Paulin R. The HIPPO-thesis of pulmonary HYPERtension. Am J Respir Crit Care Med, 2016, 194(7): 787-789.
36.	Paulin R, Michelakis ED. The metabolic theory of pulmonary arterial hypertension. Circ Res, 2014, 115(1): 148-164.
37.	Goncharov DA, Kudryashova TV, Ziai H, et al. Mammalian target of rapamycin complex 2 (mTORC2) coordinates pulmonary artery smooth muscle cell metabolism, proliferation, and survival in pulmonary arterial hypertension. Circulation, 2014, 129(8): 864-874.
38.	Serrano I, McDonald PC, Lock F, et al. Inactivation of the Hippo tumour suppressor pathway by integrin-linked kinase. Nat Commun, 2013, 4: 2976.
39.	Xiang L, Gilkes DM, Hu H, et al. HIF-1α and TAZ serve as reciprocal co-activators in human breast cancer cells. Oncotarget, 2015, 6(14): 11768-11778.
40.	Kudryashova TV, Goncharov DA, Pena A, et al. HIPPO-integrin-linked kinase cross-talk controls self-sustaining proliferation and survival in pulmonary hypertension. Am J Respir Crit Care Med, 2016, 194(7): 866-877.
41.	Shen Y, Goncharov DA, Avolio T, et al. Differential effects of integrin-linked kinase inhibitor Cpd22 on severe pulmonary hypertension in male and female rats. Pulm Circ, 2020, 10(1): 2045894019898593.
42.	Meloche J, Renard S, Provencher S, et al. Anti-inflammatory and immunosuppressive agents in PAH. Handb Exp Pharmacol, 2013, 218: 437-476.
43.	Tang F, Gill J, Ficht X, et al. The kinases NDR1/2 act downstream of the Hippo homolog MST1 to mediate both egress of thymocytes from the thymus and lymphocyte motility. Sci Signal, 2015, 8(397): ra100.
44.	Wang Q, Shi W, Zhang Q, et al. Inhibition of Siah2 ubiquitin ligase ameliorates monocrotaline-induced pulmonary arterial remodeling through inactivation of YAP. Life Sci, 2020, 242: 117159.
45.	Zhu Y, Wu Y, Shi W, et al. Inhibition of ubiquitin proteasome function prevents monocrotaline-induced pulmonary arterial remodeling. Life Sci, 2017, 173: 36-42.

1. Oliveira AC, Richards EM, Raizada MK. Pulmonary hypertension: Pathophysiology beyond the lung. Pharmacol Res, 2020, 151: 104518.
2. 中华医学会心血管病学分会肺血管病学组, 中华心血管病杂志编辑委员会. 中国肺高血压诊断和治疗指南 2018. 中华心血管病杂志, 2018, 46(12): 933-964.
3. Rosenkranz S. Pulmonary hypertension 2015: Current definitions, terminology, and novel treatment options. Clin Res Cardiol, 2015, 104(3): 197-207.
4. McClenaghan C, Woo KV, Nichols CG. Pulmonary hypertension and ATP-sensitive potassium channels. Hypertension, 2019, 74(1): 14-22.
5. Hong AW, Meng Z, Guan KL. The Hippo pathway in intestinal regeneration and disease. Nat Rev Gastroenterol Hepatol, 2016, 13(6): 324-337.
6. Calses PC, Crawford JJ, Lill JR, et al. Hippo pathway in cancer: Aberrant regulation and therapeutic opportunities. Trends Cancer, 2019, 5(5): 297-307.
7. Karaman R, Halder G. Cell junctions in Hippo signaling. Cold Spring Harb Perspect Biol, 2018, 10(5): a028753.
8. Wang J, Liu S, Heallen T, et al. The Hippo pathway in the heart: Pivotal roles in development, disease, and regeneration. Nat Rev Cardiol, 2018, 15(11): 672-684.
9. Wang W, Xiao ZD, Li X, et al. AMPK modulates Hippo pathway activity to regulate energy homeostasis. Nat Cell Biol, 2015, 17(4): 490-499.
10. Meng Z, Moroishi T, Guan KL. Mechanisms of Hippo pathway regulation. Genes Dev, 2016, 30(1): 1-17.
11. White SM, Murakami S, Yi C. The complex entanglement of Hippo-Yap/Taz signaling in tumor immunity. Oncogene, 2019, 38(16): 2899-2909.
12. Misra JR, Irvine KD. The Hippo signaling network and its biological functions. Annu Rev Genet, 2018, 52: 65-87.
13. Xu W, Yang Z, Xie C, et al. PTEN lipid phosphatase inactivation links the Hippo and PI3K/Akt pathways to induce gastric tumorigenesis. J Exp Clin Cancer Res, 2018, 37(1): 198.
14. Yu FX, Zhao B, Guan KL. Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell, 2015, 163(4): 811-828.
15. Galiè 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 Heart J, 2016, 37(1): 67-119.
16. Kondo T, Okumura N, Adachi S, et al. Pulmonary hypertension: Diagnosis, management, and treatment. Nagoya J Med Sci, 2019, 81(1): 19-30.
17. Kim D, George MP. Pulmonary hypertension. Med Clin North Am, 2019, 103(3): 413-423.
18. 钱宏, 郭应强. 左心疾病相关性肺动脉高压的研究现状. 中国胸心血管外科临床杂志, 2019, 26(4): 394-403.
19. Lücke E, Schmeißer A, Schreiber J. Pulmonary hypertension: Diagnostics, classification and therapy. Anasthesiol Intensivmed Notfallmed Schmerzther, 2019, 54(5): 320-333.
20. Dasgupta A, Wu D, Tian L, et al. Mitochondria in the pulmonary vasculature in health and disease: Oxygen-sensing, metabolism, and dynamics. Compr Physiol, 2020, 10(2): 713-765.
21. Dupont S, Morsut L, Aragona M, et al. Role of YAP/TAZ in mechanotransduction. Nature, 2011, 474(7350): 179-183.
22. He J, Bao Q, Yan M, et al. The role of Hippo/YES-associated protein signalling in vascular remodelling associated with cardiovascular disease. Br J Pharmacol, 2018, 175(8): 1354-1361.
23. Aragona M, Panciera T, Manfrin A, et al. A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors. Cell, 2013, 154(5): 1047-1059.
24. Wu D, Birukov K. Endothelial cell mechano-metabolomic coupling to disease states in the lung microvasculature. Front Bioeng Biotechnol, 2019, 7: 172.
25. Bertero T, Cottrill KA, Lu Y, et al. Matrix remodeling promotes pulmonary hypertension through feedback mechanoactivation of the YAP/TAZ-miR-130/301 circuit. Cell Rep, 2015, 13(5): 1016-1032.
26. Xie H, Wu L, Deng Z, et al. Emerging roles of YAP/TAZ in lung physiology and diseases. Life Sci, 2018, 214: 176-183.
27. Thenappan T, Chan SY, Weir EK. Role of extracellular matrix in the pathogenesis of pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol, 2018, 315(5): H1322-H1331.
28. 钱宏, 胡佳. 骨形成蛋白-4 对于肺动脉高压患者肺血管重构作用的研究进展. 中国胸心血管外科临床杂志, 2019, 26(3): 274-277.
29. Dieffenbach PB, Maracle M, Tschumperlin DJ, et al. Mechanobiological feedback in pulmonary vascular disease. Front Physiol, 2018, 9: 951.
30. Dieffenbach PB, Haeger CM, Coronata AMF, et al. Arterial stiffness induces remodeling phenotypes in pulmonary artery smooth muscle cells via YAP/TAZ-mediated repression of cyclooxygenase-2. Am J Physiol Lung Cell Mol Physiol, 2017, 313(3): L628-L647.
31. Ahmed A, Ahmed S, Arvidsson M, et al. Elevated plasma sRAGE and IGFBP7 in heart failure decrease after heart transplantation in association with haemodynamics. ESC Heart Fail, 2020, 7(5): 2340-2353.
32. Bertero T, Oldham WM, Cottrill KA, et al. Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension. J Clin Invest, 2016, 126(9): 3313-3335.
33. Ardestani A, Lupse B, Maedler K. Hippo signaling: Key emerging pathway in cellular and whole-body metabolism. Trends Endocrinol Metab, 2018, 29(7): 492-509.
34. Shi XF, Su YC. Vascular metabolic mechanisms of pulmonary hypertension. Curr Med Sci, 2020, 40(3): 444-454.
35. Boucherat O, Bonnet S, Paulin R. The HIPPO-thesis of pulmonary HYPERtension. Am J Respir Crit Care Med, 2016, 194(7): 787-789.
36. Paulin R, Michelakis ED. The metabolic theory of pulmonary arterial hypertension. Circ Res, 2014, 115(1): 148-164.
37. Goncharov DA, Kudryashova TV, Ziai H, et al. Mammalian target of rapamycin complex 2 (mTORC2) coordinates pulmonary artery smooth muscle cell metabolism, proliferation, and survival in pulmonary arterial hypertension. Circulation, 2014, 129(8): 864-874.
38. Serrano I, McDonald PC, Lock F, et al. Inactivation of the Hippo tumour suppressor pathway by integrin-linked kinase. Nat Commun, 2013, 4: 2976.
39. Xiang L, Gilkes DM, Hu H, et al. HIF-1α and TAZ serve as reciprocal co-activators in human breast cancer cells. Oncotarget, 2015, 6(14): 11768-11778.
40. Kudryashova TV, Goncharov DA, Pena A, et al. HIPPO-integrin-linked kinase cross-talk controls self-sustaining proliferation and survival in pulmonary hypertension. Am J Respir Crit Care Med, 2016, 194(7): 866-877.
41. Shen Y, Goncharov DA, Avolio T, et al. Differential effects of integrin-linked kinase inhibitor Cpd22 on severe pulmonary hypertension in male and female rats. Pulm Circ, 2020, 10(1): 2045894019898593.
42. Meloche J, Renard S, Provencher S, et al. Anti-inflammatory and immunosuppressive agents in PAH. Handb Exp Pharmacol, 2013, 218: 437-476.
43. Tang F, Gill J, Ficht X, et al. The kinases NDR1/2 act downstream of the Hippo homolog MST1 to mediate both egress of thymocytes from the thymus and lymphocyte motility. Sci Signal, 2015, 8(397): ra100.
44. Wang Q, Shi W, Zhang Q, et al. Inhibition of Siah2 ubiquitin ligase ameliorates monocrotaline-induced pulmonary arterial remodeling through inactivation of YAP. Life Sci, 2020, 242: 117159.
45. Zhu Y, Wu Y, Shi W, et al. Inhibition of ubiquitin proteasome function prevents monocrotaline-induced pulmonary arterial remodeling. Life Sci, 2017, 173: 36-42.

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