Association between ACE2/ACE balance and pneumocyte apoptosis in a porcine model of acute pulmonary thromboembolism with cardiac arrest

Xiao,Hong‑Li; Zhao,Lian‑Xing; Yang,Jun; Tong,Nan; An,Le; Liu,Qi‑Tong; Xie,Miao‑Rong; Li,Chun‑Sheng

doi:10.3892/mmr.2018.8426

Association between ACE2/ACE balance and pneumocyte apoptosis in a porcine model of acute pulmonary thromboembolism with cardiac arrest

Authors:
- Hong‑Li Xiao
- Lian‑Xing Zhao
- Jun Yang
- Nan Tong
- Le An
- Qi‑Tong Liu
- Miao‑Rong Xie
- Chun‑Sheng Li
View Affiliations

Affiliations: Department of Emergency Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China, Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Beijing Chao‑Yang Hospital, Capital Medical University, Beijing 100020, P.R. China, Department of Radiology, Beijing Chao‑Yang Hospital, Capital Medical University, Beijing 100020, P.R. China
Published online on: January 12, 2018 https://doi.org/10.3892/mmr.2018.8426
Pages: 4221-4228
Copyright: © Xiao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Acute pulmonary embolism (APE) is frequently reported in patients with cardiac arrest (CA) in emergency care. Pneumocyte apoptosis is commonly observed in the lungs following an APE. An important pathological mechanism evoking apoptosis during a lipopolysaccharide‑induced acute lung injury is the angiotensin‑converting enzyme 2 (ACE2)/ACE imbalance. The present study uses a porcine model to examine the anti‑apoptotic effects of captopril on APE‑CA and the return of spontaneous circulation (ROSC). Pigs were randomly assigned into four groups: Control, APE‑CA, ROSC‑saline, and ROSC‑captopril. Surviving pigs were euthanized at 6 h and lungs were isolated for analysis using several biochemical assays. Compared with the control group, the ACE2/ACE ratio was lower in the APE‑CA and ROSC pigs. In addition, APE‑CA pigs had higher Bcl‑2‑associated X protein (Bax) and cleaved caspase‑3 levels, and lower B‑cell lymphoma‑2 (Bcl‑2) level compared to control pigs. Captopril treatment reduced lung apoptosis, as demonstrated by lower TUNEL‑positive cells, higher Bcl‑2, and lower cleaved caspase‑3 protein levels in the lung. Notably, the ACE2/ACE ratio was positively correlated with Bcl‑2 protein levels and Bcl‑2/Bax ratio. In conclusion, captopril has a protective effect against lung apoptosis following ROSC and that maintaining the balance of the ACE2/ACE axis is important for inhibiting pulmonary apoptosis during APE.

View Figures

View References

1	Chesnutt MS, Prendergast TJ, McPhee SJ, Papadakis MA and Tierney LM Jr: Pulmonary venous thromboembolismCurrent Medical Diagnosis and Treatment. 46th. New York McGraw Hill; 28. pp. 284–294. 2007
2	Kuisma M and Alaspää A: Out-of-hospital cardiac arrests of non-cardiac origin. Epidemiology and outcome. Eur Heart J. 18:1122–1128. 1997. View Article : Google Scholar : PubMed/NCBI
3	Li SQ, Jian W, Liu AR, Zhao F, Ti XY and Ouyang HF: Expression of apoptosis related protein in transforming growth factors-beta signaling pathway and its effects on the cell apoptosis in the lung tissues after acute pulmonary embolism. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 20:353–356. 2008.(In Chinese). PubMed/NCBI
4	Fischer S, Cassivi SD, Xavier AM, Cardella JA, Cutz E, Xavier AM, Edwards V, Liu M and Keshavjee S: Cell death in human lung transplantation: Apoptosis induction in human lungs during ischemia and after transplantation. Ann Surg. 231:424–431. 2000. View Article : Google Scholar : PubMed/NCBI
5	Van Putte BP, Kesecioglu J, Hendriks JM, Persy VP, van Marck E, van Schil P and Broe ME: Cellular infiltrates and injury evaluation in a rat model of warm pulmonary ischemia-reperfusion. Crit Care. 9:R1–R8. 2005. View Article : Google Scholar : PubMed/NCBI
6	Bargout R, Jankov A, Dincer E, Ibarra-Sunga O, Komodromos T, Filippatos G and Uhal BD: Amiodarone induces apoptosis in human and rat alveolar epithelial cells in vitro. Am J Physiol Lung Cell MolPhysiol. 278:L1039–L1044. 2000. View Article : Google Scholar
7	Wang R, Ibarra-Sunga O, Verlinski L, Pick R and Uhal BD: Abrogation of bleomycin-induced epithelial apoptosis and lung fibrosis by captopril or by a caspase inhibitor. Am J Physiol Lung Cell MolPhysiol. 279:L143–L151. 2000. View Article : Google Scholar
8	Wang L, Wang Y, Yang T, Guo Y and Sun T: Angiotensin-Converting Enzyme 2 attenuates Bleomycin-induced lung fibrosis in mice. Cell Physiol Biochem. 36:697–711. 2015. View Article : Google Scholar : PubMed/NCBI
9	Ji Y, Gao F, Sun B, Hao J and Liu Z: Angiotensin-converting enzyme 2 inhibits apoptosis of pulmonary endothelial cells during acute lung injury through suppressing SMAD2 phosphorylation. Cell Physiol Biochem. 35:2203–2212. 2015. View Article : Google Scholar : PubMed/NCBI
10	Xiao HL, Li CS, Zhao LX, Yang J, Tong N, An L and Liu QT: Captopril improves postresuscitation hemodynamics protective against pulmonary embolism by activating the ACE2/Ang-(1–7)/Mas axis. Naunyn Schmiedebergs Arch Pharmacol. 389:1159–1169. 2016. View Article : Google Scholar : PubMed/NCBI
11	Pantazopoulos IN, Xanthos TT, Vlachos I, Troupis G, Kotsiomitis E, Johnson E, Papalois A and Skandalakis P: Use of the impedance threshold device improves survival rate and neurological outcome in a swine model of asphyxial cardiac arrest. Crit Care Med. 40:861–868. 2012. View Article : Google Scholar : PubMed/NCBI
12	Travers AH, Rea TD, Bobrow BJ, Edelson DP, Berg RA, Sayre MR, Berg MD, Chameides L, O'Connor RE and Swor RA: Part 4: CPR overview: 2010 American heart association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 122 18 Suppl 3:S676–S684. 2010. View Article : Google Scholar : PubMed/NCBI
13	Stadlbauer KH, Rheinberger K, Wenzel V, Raedler C, Krismer AC, Strohmenger HU, Augenstein S, Wagner-Berger HG, Voelckel WG, Lindner KH and Amann A: The effects of nifedipine on ventricular fibrillation mean frequency in a porcine model of prolonged cardiopulmonary resuscitation. Anesth Analg. 97:226–230. 2003. View Article : Google Scholar : PubMed/NCBI
14	Deng C, Yang M, Lin Q, Yang Y, Zhai Z, Liu K, Ding H, Cao X, Huang Z, Zhang L and Zhao J: Beneficial effects of inhaled NO on apoptotic pneumocytes in pulmonary thromboembolism model. Theor Biol Med Model. 11:362014. View Article : Google Scholar : PubMed/NCBI
15	Hagimoto N, Kuwano K, Miyazaki H, Kunitake R, Fujita M, Kawasaki M, Kanika Y and Hara N: Induction of apoptosis and pulmonary fibrosis in mice in response to ligation of FAS antigen. Am J Respir Cell MolBiol. 17:272–278. 1997. View Article : Google Scholar
16	Kuwano K, Kunitake R, Kawasaki M, Nomoto Y, Hagimoto N, Nakanishi Y and Hara N: P21Waf1/Cip1/Sdi1 and p53 expression in association with DNA strand breaks in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 154:477–483. 1996. View Article : Google Scholar : PubMed/NCBI
17	Matute-Bello G, Liles WC, Steinberg KP, Kiener PA, Mongovin S, Chi EY, Jonas M and Martin TR: Soluble Fas ligand induces epithelial cell apoptosis in humans with acute lung injury (ARDS). J Immunol. 163:2217–2225. 1999.PubMed/NCBI
18	Segura-Valdez L, Pardo A, Gaxiola M, Uhal BD, Becerril C and Selman M: Upregulation of gelatinases A and B, collagenases 1 and 2, and increased parenchymal cell death in COPD. Chest. 117:684–694. 2000. View Article : Google Scholar : PubMed/NCBI
19	Wagner EM, Petrache I, Schofield B and Mitzner W: Pulmonary ischemia induces lung remodeling and angiogenesis. J Appl Physiol (1985). 100:587–593. 2006. View Article : Google Scholar : PubMed/NCBI
20	Mercier O, Sage E, de Perrot M, Tu L, Marcos E, Decante B, Baudet B, Hervé P, Dartevelle P, Eddahibi S and Fadel E: Regression of flow-induced pulmonary arterial vasculopathy after flow correction in piglets. J Thorac Cardiovasc Surg. 137:1538–1546. 2009. View Article : Google Scholar : PubMed/NCBI
21	Dolkart O.E.A.S.S.S.M.P.G..Aa W: Temporal determination of lung NO system and COX-2 upregulation following ischemia-reperfusion injury. Exp Lung Res. 40:22–29. 2014. View Article : Google Scholar : PubMed/NCBI
22	Deng C, Zhai Z, Wu D, Lin Q, Yang Y, Yang M, Ding H, Cao X, Zhang Q and Wang C: Inflammatory response and pneumocyte apoptosis during lung ischemia-reperfusion injury in an experimental pulmonary thromboembolism model. J Thromb Thrombolysis. 40:42–53. 2015. View Article : Google Scholar : PubMed/NCBI
23	Deng W, Deng Y, Deng J, Wang DX and Zhang T: Losartan attenuated lipopolysaccharide-induced lung injury by suppression of lectin-like oxidized low-density lipoprotein receptor-1. Int J Clin Exp Pathol. 8:15670–15676. 2015.PubMed/NCBI
24	Yang HY, Bian YF, Zhang HP, Gao F, Xiao CS, Liang B, Li J, Zhang NN and Yang ZM: Angiotensin-(1–7) treatment ameliorates angiotensin II-induced apoptosis of human umbilical vein endothelial cells. Clin Exp Pharmacol Physiol. 39:1004–1010. 2012. View Article : Google Scholar : PubMed/NCBI
25	Li Y, Cao Y, Zeng Z, Liang M, Xue Y, Xi C, Zhou M and Jiang W: Angiotensin-converting enzyme 2/angiotensin-(1–7)/Mas axis prevents lipopolysaccharide-induced apoptosis of pulmonary microvascular endothelial cells by inhibiting JNK/NF-κB pathways. Sci Rep. 5:82092015. View Article : Google Scholar : PubMed/NCBI
26	Gowrisankar YV and Clark MA: Angiotensin II regulation of angiotensin-converting enzymes in spontaneously hypertensive rat primary astrocyte cultures. J Neurochem. 138:74–85. 2016. View Article : Google Scholar : PubMed/NCBI
27	Gaddam RR, Ang AD, Badiei A, Chambers ST and Bhatia M: Alteration of the renin-angiotensin system in caerulein induced acute pancreatitis in the mouse. Pancreatology. 15:647–653. 2015. View Article : Google Scholar : PubMed/NCBI
28	Liu R, Qi H, Wang J, Wang Y, Cui L, Wen Y and Yin C: Angiotensin-converting enzyme (ACE and ACE2) imbalance correlates with the severity of cerulein-induced acute pancreatitis in mice. Exp Physiol. 99:651–663. 2014. View Article : Google Scholar : PubMed/NCBI
29	Moreira de Macêdo S, Guimarães TA, Feltenberger JD and Sousa Santos SH: The role of renin-angiotensin system modulation on treatment and prevention of liver diseases. Peptides. 62:189–196. 2014. View Article : Google Scholar : PubMed/NCBI
30	Yang XH, Wang YH, Wang JJ, Liu YC, Deng W, Qin C, Gao JL and Zhang LY: Role of angiotensin-converting enzyme (ACE and ACE2) imbalance on tourniquet-induced remote kidney injury in a mouse hindlimb ischemia-reperfusion model. Peptides. 36:60–70. 2012. View Article : Google Scholar : PubMed/NCBI
31	Fan L, Feng Y, Wan HY, Ni L, Qian YR, Guo Y, Xiang Y and Li QY: Hypoxia induces dysregulation of local renin-angiotensin system in mouse Lewis lung carcinoma cells. Genet Mol Res. 13:10562–10573. 2014. View Article : Google Scholar : PubMed/NCBI
32	Li Y, Zeng Z, Li Y, Huang W, Zhou M, Zhang X and Jiang W: Angiotensin-converting enzyme inhibition attenuates lipopolysaccharide-induced lung injury by regulating the balance between angiotensin-converting enzyme and angiotensin-converting enzyme 2 and inhibiting mitogen-activated protein kinase activation. Shock. 43:395–404. 2015. View Article : Google Scholar : PubMed/NCBI