The Effect of Different Numbers of Bone Marrow Mesenchymal Stem Cells Transplanted into Rats with Pulmonary Arterial Hypertension and Their Influence on Endothelin-1 Expression_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

ZHAO Keyan , WANG Huishan , HOU Mingxiao

1. Department of Cardiovascular Surgery，General Hospital of Shenyang Military Region，Shenyang 110016，P. R. China;;
2. Department of Cardiovascular Surgery，the Second Hospital of Jilin University，Changchun 130041，P. R. China;

Corresponding author：

Keywords：

Bone marrow mesenchymal stem cell; Pulmonary hypertension; Monocrotaline; Cell transplantation

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

Abstract： Objective To study the effect of different numbers of bone marrow mesenchymal stem cells（MSCs） transplanted into rats with pulmonary arterial hypertension （PAH）induced by monocrotaline（MCT）and their influence on the expression of endothelin-1（ET-1）. Methods Forty healthy male Wistar rats（weight，from 180 to 250 g） were divided into four groups by random number table（n=10）：group A：Wistar rats were intraperitoneally injected with MCT 60 mg/ kg， and then injected with 1×106 MSCs via the external jugular vein；group B：Wistar rats were intraperitoneally injected with MCT 60 mg/kg，and then injected with 5×105 MSCs via the external jugular vein；MCT group：Wistar rats were
intraperitoneally injected with MCT 60 mg/kg， and then injected with equal amount of PBS via the external jugular vein； control group：Wistar rats were intraperitoneally injected with equal amount of saline and then injected with equal amount of PBS via the external jugular vein. Four weeks after MSCs transplantation，right ventricular systolic pressure（RVSP） and ventricular weight ratio of right ventricle/ （left ventricle＋ventricular septum）were measured. Histomorphology of lung tissue was observed. Genetic expression of ET-1 in lungs and serum peptide of ET-1 were also measured. Results Four weeks after MSCs transplantation，both RVSP and ventricular weight ratio decreased significantly in rats of group Acompared with those of MCT group（RVSP：35.8±4.2 mm Hg vs. 47.2±10.1 mm Hg，P＜ 0.01； ventricular weight ratio：0.357±0.032 vs. 0.452±0.056，P＜0.01）， but these two parameters didn’t decrease significantly in rats of group B（P＞ 0.05）. By histopathological staining， the percentage of medial wall thickness of the pulmonary arterioles was significantly less in rats of group A than that of MCT group（19.7%±3.0% vs. 26.8%±3.6%， P＜ 0.01）. There was no statistical difference in the percentage of medial wall thickness of the pulmonary arterioles between group B and MCT group. Reverse transcriptase-polymerase chain reaction （RTase-PCR）results showed that ET-1messenger ribonucleic acid（mRNA）expression was highest in MCT group and MSCs transplantation significantly decreasedits expression in group A， while its expression was similar between group B and MCT group. The expression ofET-1 in plasma was also significantly decreased in group A than that in MCT group. Conclusion Intravenous MSCs transplantation can significantly inhibit MCT-induced PAH，and reduce both ET-1 mRNA expression in lung and ET-1 peptide level in plasma. It’s a better choice to transplant 1×106 MSCs to inhibit PAH in rats.

Citation： ZHAO Keyan,WANG Huishan,HOU Mingxiao,et al.. The Effect of Different Numbers of Bone Marrow Mesenchymal Stem Cells Transplanted into Rats with Pulmonary Arterial Hypertension and Their Influence on Endothelin-1 Expression. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2012, 19(3): 298-303. doi: Copy

1.	Tuder RM， Marecki JC， Richter A， et al. Pathology of pulmonary hypertension. Clin Chest Med， 2007， 28 （1）：23-42， vii.
2.	Rubin LJ. Pathology and pathophysiology of primary pulmonary hypertension. Am J Cardiol， 1995， 75 （3）：51A-54A.
3.	Lammers AE， Hislop AA， Flynn Y， et al. Epoprostenol treatment in children with severe pulmonary hypertension. Heart， 2007， 93 （6）：739-743.
4.	Galiè N， Beghetti M， Gatzoulis MA， et al. Bosentan therapy in patients with Eisenmenger syndrome：a multicenter， double-blind， randomized， placebo-controlled study. Circulation， 2006， 114 （1）：48-54.
5.	Chau EM， Fan KY， Chow WH. Effects of chronic sildenafil in patients with Eisenmenger syndrome versus idiopathic pulmonary arterial hypertension. Int J Cardiol， 2007， 120 （3）：301-305.
6.	王峰，肖明第，廖斌，等. 小肠黏膜下层-骨髓间充质干细胞移植治疗陈旧性心肌梗死. 中国胸心血管外科临床杂志， 2010， 17 （4）：344-346.
7.	Hou M， Yang KM， Zhang H， et al. Transplantation of mesenchymal stem cells from human bone marrow improves damaged heart function in rats. Int J Cardiol， 2007， 115 （2）：220-228.
8.	Yip HK， Chang LT， Sun CK， et al. Autologous transplantation of bone marrow-derived endothelial progenitor cells attenuates monocrotaline-induced pulmonary arterial hypertension in rats. Crit Care Med， 2008， 36 （3）：873-880.
9.	Zhao YD， Courtman DW， Deng Y， et al. Rescue of monocrotaline-induced pulmonary arterial hypertension using bone marrow-derived endothelial-like progenitor cells：efficacy of combined cell and eNOS gene therapy in established disease. Circ Res， 2005， 96 （4）：442- 450.
10.	Oishi P， Fineman J. Pulmoanry endothelial control of pulmonary microcirculation. In：Redington A， Van-Arsdell G， Anderson RH. Congenital Diseases in the Right Heart. London：Springer-Verlag， 2009. 29-37.
11.	Shao D， Park JE， Wort SJ. The role of endothelin-1 in the pathogenesis of pulmonary arterial hypertension. Pharmacol Res， 2011， 63 （6）：504-511.
12.	张冰，程罡，刘洪英，等. 一种糖尿病-高血压大鼠模型的建立. 药学学报， 2009， 44 （6）：575-580.
13.	Voelkel NF， Cool C. Pathology of pulmonary hypertension. Cardiol Clin， 2004， 22 （3）：343-351.
14.	Giaid A， Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med， 1995， 333 （4）：214-221.
15.	Wedgwood S， Dettman RW， Black SM. ET-1 stimulates pulmonary arterial smooth muscle cell proliferation via induction of reactive oxygen species. Am J Physiol Lung Cell Mol Physiol， 2001， 281 （5）：L1058-L1067.
16.	顾勇，王治平，鲁建军，等. 野百合碱所致肺动脉高压大鼠模型中碱性成纤维细胞生长因子、内皮素-1及其受体的表达和外源性NO的作用. 中国病理生理杂志， 2003， 19 （10）：1416-1417.
17.	Yao Y， Zhang F， Wang L， et al. Lipopolysaccharide preconditioning enhances the efficacy of mesenchymal stem cells transplantation in a rat model of acute myocardial infarction. J Biomed Sci， 2009，16：74-82.
18.	何凤璞，汪黎明，陈文，等. 大鼠骨髓间充质干细胞体外诱导分化为血管平滑肌样细胞的实验研究. 中国胸心血管外科临床杂志， 2011， 18 （3）：236-239.
19.	Nagaya N， Kangawa K， Kanda M， et al. Hybrid cell-gene therapy for pulmonary hypertension based on phagocytosing action of endothelial progenitor cells. Circulation， 2003， 108 （7）：889-895.
20.	Campbell AI， Kuliszewski MA， Stewart DJ. Cell-based gene transfer to the pulmonary vasculature：Endothelial nitric oxide synthase overexpression inhibits monocrotaline-induced pulmonary hypertension. Am J Respir Cell Mol Biol， 1999， 21 （5）：567-575.
21.	Ortiz LA， Gambelli F， McBride C， et al. Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci USA， 2003， 100 （14）：8407-8411.
22.	Baber SR， Deng W， Master RG， et al. Intratracheal mesenchymal stem cell administration attenuates monocrotaline-induced pulmonary hypertension and endothelial dysfunction. Am J Physiol Heart Circ Physiol， 2007， 292 （2）：H1120-H1128.
23.	Patel KM， Crisostomo P， Lahm T， et al. Mesenchymal stem cells attenuate hypoxic pulmonary vasoconstriction by a paracrine mechanism. J Surg Res， 2007， 143 （2）：281-285.
24.	Ward MR， Stewart DJ， Kutryk MJ. Endothelial progenitor cell therapy for the treatment of coronary disease， acute MI， and pulmonary arterial hypertension：current perspectives. Catheter Cardiovasc Interv， 2007，70 （7）：983-998.
25.	Kanki-Horimoto S， Horimoto H， Mieno S， et al. Implantation of mesenchymal stem cells overexpressing endothelial nitric oxide synthase improves right ventricular impairments caused by pulmonary hypertension. Circulation， 2006， 114 （1 Suppl）：I181-I185.
26.	Stewart DJ， Levy RD， Cernacek P， et al. Increased plasma endothelin-1 in pulmonary hypertension：marker or mediator of disease? Ann Intern Med， 1991， 114 （6）：464-469.
27.	Giaid A， Yanagisawa M， Langleben D， et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension.N Engl J Med， 1993， 328 （24）：1732-1739.
28.	Schermuly RT， Ghofrani HA， Wilkins MR， et al. Mechanisms of disease：pulmonary arterial hypertension. Nat Rev Cardiol， 2011，8 （8）：443-455.
29.	何志旭，汪浩文，尚峰，等. 骨髓间充质干细胞移植治疗实验性肺动脉高压大鼠血流动力学指标的变化. 实用儿科临床杂志， 2009， 24 （1）：14-17.
30.	何志旭，汪浩文，尚峰，等. 骨髓间充质干细胞治疗实验性肺动脉高压后肺组织结构的变化. 中国病理生理杂志， 2009， 25 （10）：1907-1911.

1. 　Tuder RM， Marecki JC， Richter A， et al. Pathology of pulmonary hypertension. Clin Chest Med， 2007， 28 （1）：23-42， vii.
2. 　Rubin LJ. Pathology and pathophysiology of primary pulmonary hypertension. Am J Cardiol， 1995， 75 （3）：51A-54A.
3. 　Lammers AE， Hislop AA， Flynn Y， et al. Epoprostenol treatment in children with severe pulmonary hypertension. Heart， 2007， 93 （6）：739-743.
4. 　Galiè N， Beghetti M， Gatzoulis MA， et al. Bosentan therapy in patients with Eisenmenger syndrome：a multicenter， double-blind， randomized， placebo-controlled study. Circulation， 2006， 114 （1）：48-54.
5. 　Chau EM， Fan KY， Chow WH. Effects of chronic sildenafil in patients with Eisenmenger syndrome versus idiopathic pulmonary arterial hypertension. Int J Cardiol， 2007， 120 （3）：301-305.
6. 　王峰，肖明第，廖斌，等. 小肠黏膜下层-骨髓间充质干细胞移植治疗陈旧性心肌梗死. 中国胸心血管外科临床杂志， 2010， 17 （4）：344-346.
7. 　Hou M， Yang KM， Zhang H， et al. Transplantation of mesenchymal stem cells from human bone marrow improves damaged heart function in rats. Int J Cardiol， 2007， 115 （2）：220-228.
8. 　Yip HK， Chang LT， Sun CK， et al. Autologous transplantation of bone marrow-derived endothelial progenitor cells attenuates monocrotaline-induced pulmonary arterial hypertension in rats. Crit Care Med， 2008， 36 （3）：873-880.
9. 　Zhao YD， Courtman DW， Deng Y， et al. Rescue of monocrotaline-induced pulmonary arterial hypertension using bone marrow-derived endothelial-like progenitor cells：efficacy of combined cell and eNOS gene therapy in established disease. Circ Res， 2005， 96 （4）：442- 450.
10. 　Oishi P， Fineman J. Pulmoanry endothelial control of pulmonary microcirculation. In：Redington A， Van-Arsdell G， Anderson RH. Congenital Diseases in the Right Heart. London：Springer-Verlag， 2009. 29-37.
11. 　Shao D， Park JE， Wort SJ. The role of endothelin-1 in the pathogenesis of pulmonary arterial hypertension. Pharmacol Res， 2011， 63 （6）：504-511.
12. 　张冰，程罡，刘洪英，等. 一种糖尿病-高血压大鼠模型的建立. 药学学报， 2009， 44 （6）：575-580.
13. 　Voelkel NF， Cool C. Pathology of pulmonary hypertension. Cardiol Clin， 2004， 22 （3）：343-351.
14. 　Giaid A， Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med， 1995， 333 （4）：214-221.
15. 　Wedgwood S， Dettman RW， Black SM. ET-1 stimulates pulmonary arterial smooth muscle cell proliferation via induction of reactive oxygen species. Am J Physiol Lung Cell Mol Physiol， 2001， 281 （5）：L1058-L1067.
16. 　顾勇，王治平，鲁建军，等. 野百合碱所致肺动脉高压大鼠模型中碱性成纤维细胞生长因子、内皮素-1及其受体的表达和外源性NO的作用. 中国病理生理杂志， 2003， 19 （10）：1416-1417.
17. 　Yao Y， Zhang F， Wang L， et al. Lipopolysaccharide preconditioning enhances the efficacy of mesenchymal stem cells transplantation in a rat model of acute myocardial infarction. J Biomed Sci， 2009，16：74-82.
18. 　何凤璞，汪黎明，陈文，等. 大鼠骨髓间充质干细胞体外诱导分化为血管平滑肌样细胞的实验研究. 中国胸心血管外科临床杂志， 2011， 18 （3）：236-239.
19. 　Nagaya N， Kangawa K， Kanda M， et al. Hybrid cell-gene therapy for pulmonary hypertension based on phagocytosing action of endothelial progenitor cells. Circulation， 2003， 108 （7）：889-895.
20. 　Campbell AI， Kuliszewski MA， Stewart DJ. Cell-based gene transfer to the pulmonary vasculature：Endothelial nitric oxide synthase overexpression inhibits monocrotaline-induced pulmonary hypertension. Am J Respir Cell Mol Biol， 1999， 21 （5）：567-575.
21. 　Ortiz LA， Gambelli F， McBride C， et al. Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci USA， 2003， 100 （14）：8407-8411.
22. 　Baber SR， Deng W， Master RG， et al. Intratracheal mesenchymal stem cell administration attenuates monocrotaline-induced pulmonary hypertension and endothelial dysfunction. Am J Physiol Heart Circ Physiol， 2007， 292 （2）：H1120-H1128.
23. 　Patel KM， Crisostomo P， Lahm T， et al. Mesenchymal stem cells attenuate hypoxic pulmonary vasoconstriction by a paracrine mechanism. J Surg Res， 2007， 143 （2）：281-285.
24. 　Ward MR， Stewart DJ， Kutryk MJ. Endothelial progenitor cell therapy for the treatment of coronary disease， acute MI， and pulmonary arterial hypertension：current perspectives. Catheter Cardiovasc Interv， 2007，70 （7）：983-998.
25. 　Kanki-Horimoto S， Horimoto H， Mieno S， et al. Implantation of mesenchymal stem cells overexpressing endothelial nitric oxide synthase improves right ventricular impairments caused by pulmonary hypertension. Circulation， 2006， 114 （1 Suppl）：I181-I185.
26. 　Stewart DJ， Levy RD， Cernacek P， et al. Increased plasma endothelin-1 in pulmonary hypertension：marker or mediator of disease? Ann Intern Med， 1991， 114 （6）：464-469.
27. 　Giaid A， Yanagisawa M， Langleben D， et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension.N Engl J Med， 1993， 328 （24）：1732-1739.
28. 　Schermuly RT， Ghofrani HA， Wilkins MR， et al. Mechanisms of disease：pulmonary arterial hypertension. Nat Rev Cardiol， 2011，8 （8）：443-455.
29. 　何志旭，汪浩文，尚峰，等. 骨髓间充质干细胞移植治疗实验性肺动脉高压大鼠血流动力学指标的变化. 实用儿科临床杂志， 2009， 24 （1）：14-17.
30. 　何志旭，汪浩文，尚峰，等. 骨髓间充质干细胞治疗实验性肺动脉高压后肺组织结构的变化. 中国病理生理杂志， 2009， 25 （10）：1907-1911.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

The Effect of Different Numbers of Bone Marrow Mesenchymal Stem Cells Transplanted into Rats with Pulmonary Arterial Hypertension and Their Influence on Endothelin-1 Expression

Abstract Full text Figures/Tables Video References Cited by

Format

Content