Cpt1a alleviates cigarette smoke‑induced chronic obstructive pulmonary disease

Li,Lifang; Li,Lifang; Zhang,Yaqian; Zhang,Yaqian; Gong,Jiannan; Gong,Jiannan; Yang,Guang; Yang,Guang; Zhi,Shuyin; Zhi,Shuyin; Ren,Dongping; Ren,Dongping; Zhao,Hui; Zhao,Hui

doi:10.3892/etm.2022.11753

Cpt1a alleviates cigarette smoke‑induced chronic obstructive pulmonary disease

Authors:
- Lifang Li
- Yaqian Zhang
- Jiannan Gong
- Guang Yang
- Shuyin Zhi
- Dongping Ren
- Hui Zhao
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Affiliations: Department of Respiratory and Critical Care Medicine, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China, School of Basic Medical Sciences, Department of Pharmacology, Shanxi Medical University, Taiyuan 030000, P.R. China, Department of R&D, USBAY Biotechnology Co., Ltd, Beijing 102006, P.R. China
Published online on: December 7, 2022 https://doi.org/10.3892/etm.2022.11753
Article Number: 54
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The current study aimed to determine the expression of carnitine palmitoyltransferase 1A (Cpt1a) in the lung tissue of chronic obstructive pulmonary disease (COPD) patients and its correlation with lung function. An increase in Cpt1a expression improved lung function in patients with COPD by inhibiting apoptosis and the inflammatory response of lung endothelial cells. Lung tissues of 20 patients with COPD and 10 control patients were collected, their Cpt1a expression was determined by western blotting and apoptosis and inflammation were assessed by haematoxylin‑eosin staining, TUNEL assay and ELISA. Mice with knockout or overexpression of Cpt1a were constructed by lentivirus in vivo. A COPD model was induced by cigarette smoke and the role of Cpt1a in COPD was determined in vivo and in vitro. Cpt1a expression was positively correlated with lung function and negatively correlated with apoptosis and inflammation. Patients with COPD with higher expression of Cpt1a in lung tissues had improved lung function indices and lung tissue morphology with less apoptosis and decreased inflammatory response. Compared with the control group, COPD mice with Cpt1a knockdown had aggravated lung dysfunction and increased lung inflammation and apoptosis. Overexpression of Cpt1a alleviated lung dysfunction and reduced inflammatory response and apoptosis of lung tissues in COPD mice. Pulmonary microvascular endothelial cells of mice were isolated in vitro and the results were consistent with the findings obtained in vivo. In conclusion, the clinical, in vivo and in vitro data confirmed for the first time that Cpt1a alleviated lung dysfunction of patients with COPD by inhibiting apoptosis of endothelial cells and inflammatory responses.

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1	Lareau SC, Fahy B, Meek P and Wang A: Chronic obstructive pulmonary disease (COPD). Am J Respir Crit Care Med. 199:P1–P2. 2019.PubMed/NCBI View Article : Google Scholar
2	Mannino DM and Buist AS: Global burden of COPD: Risk factors, prevalence, and future trends. Lancet. 370:765–773. 2007.PubMed/NCBI View Article : Google Scholar
3	Rao W, Wang S, Duleba M, Niroula S, Goller K, Xie J, Mahalingam R, Neupane R, Liew AA, Vincent M, et al: Regenerative metaplastic clones in COPD lung drive inflammation and fibrosis. Cell. 181:848–864. 2020.PubMed/NCBI View Article : Google Scholar
4	Hisata S, Racanelli AC, Kermani P, Schreiner R, Houghton S, Palikuqi B, Kunar B, Zhou A, McConn K, Capili A, et al: Reversal of emphysema by restoration of pulmonary endothelial cells. J Exp Med. 218(e20200938)2021.PubMed/NCBI View Article : Google Scholar
5	Raud B, Roy DG, Divakaruni AS, Tarasenko TN, Franke R, Ma EH, Samborska B, Hsieh WY, Wong AH, Stüve P, et al: Etomoxir actions on regulatory and memory T cells are independent of Cpt1a-mediated fatty acid oxidation. Cell Metab. 28:504–515. 2018.PubMed/NCBI View Article : Google Scholar
6	Yao H, Gong J, Peterson AL, Lu X, Zhang P and Dennery PA: Fatty acid oxidation protects against hyperoxia-induced endothelial cell apoptosis and lung injury in neonatal mice. Am J Respir Cell Mol Biol. 60:667–677. 2019.PubMed/NCBI View Article : Google Scholar
7	Gong J, Zhao H, Liu T, Li L, Cheng E, Zhi S, Kong L, Yao W and Li J: Cigarette smoke reduces fatty acid catabolism, leading to apoptosis in lung endothelial cells: Implication for pathogenesis of COPD. Front Pharmacol. 10(941)2019.PubMed/NCBI View Article : Google Scholar
8	Schoors S, Bruning U, Missiaen R, Queiroz KC, Borgers G, Elia I, Zecchin A, Cantelmo AR, Christen S, Goveia J, et al: Fatty acid carbon is essential for dNTP synthesis in endothelial cells. Nature. 520:192–197. 2015.PubMed/NCBI View Article : Google Scholar
9	Yao RQ, Ren C, Xia ZF and Yao YM: Organelle-specific autophagy in inflammatory diseases: A potential therapeutic target underlying the quality control of multiple organelles. Autophagy. 17:385–401. 2021.PubMed/NCBI View Article : Google Scholar
10	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar
11	Çolak Y, Afzal S, Nordestgaard BG, Lange P and Vestbo J: Importance of early COPD in young adults for development of clinical COPD: Findings from the copenhagen general population study. Am J Respir Crit Care Med. 203:1245–1256. 2021.PubMed/NCBI View Article : Google Scholar
12	Wong J, Magun BE and Wood LJ: Lung inflammation caused by inhaled toxicants: A review. Int J Chron Obstruct Pulmon Dis. 11:1391–401. 2016.PubMed/NCBI View Article : Google Scholar
13	Li F, Jiang T, Li Q and Ling X: Camptothecin (CPT) and its derivatives are known to target topoisomerase I (Top1) as their mechanism of action: Did we miss something in CPT analogue molecular targets for treating human disease such as cancer? Am J Cancer Res. 7:2350–2394. 2017.PubMed/NCBI
14	Bonnefont JP, Djouadi F, Prip-Buus C, Gobin S, Munnich A and Bastin J: Carnitine palmitoyltransferases 1 and 2: Biochemical, molecular and medical aspects. Mol Aspects Med. 25:495–520. 2004.PubMed/NCBI View Article : Google Scholar
15	Casals N, Zammit V, Herrero L, Fadó R, Rodríguez-Rodríguez R and Serra D: Carnitine palmitoyltransferase 1C: From cognition to cancer. Prog Lipid Res. 61:134–148. 2016.PubMed/NCBI View Article : Google Scholar
16	Wolfgang MJ, Kurama T, Dai Y, Suwa A, Asaumi M, Matsumoto SI, Cha SH, Shimokawa T and Lane MD: The brain-specific carnitine palmitoyltransferase-1c regulates energy homeostasis. Proc Natl Acad Sci USA. 103:7282–7287. 2006.PubMed/NCBI View Article : Google Scholar
17	Gao XF, Chen W, Kong XP, Xu AM, Wang ZG, Sweeney G and Wu D: Enhanced susceptibility of Cpt1c knockout mice to glucose intolerance induced by a high-fat diet involves elevated hepatic gluconeogenesis and decreased skeletal muscle glucose uptake. Diabetologia. 52:912–920. 2009.PubMed/NCBI View Article : Google Scholar
18	Jiang Z, Knudsen NH, Wang G, Qiu W, Naing ZZC, Bai Y, Ai X, Lee CH and Zhou X: Genetic control of fatty acid β-oxidation in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol. 56:738–748. 2017.PubMed/NCBI View Article : Google Scholar
19	Xiong X, Wen YA, Fairchild R, Zaytseva YY, Weiss HL, Evers BM and Gao T: Upregulation of CPT1A is essential for the tumor-promoting effect of adipocytes in colon cancer. Cell Death Dis. 11(736)2020.PubMed/NCBI View Article : Google Scholar
20	Tan Z, Xiao L, Tang M, Bai F, Li J, Li L, Shi F, Li N, Li Y, Du Q, et al: Targeting CPT1A-mediated fatty acid oxidation sensitizes nasopharyngeal carcinoma to radiation therapy. Theranostics. 8:2329–2347. 2018.PubMed/NCBI View Article : Google Scholar
21	Hecht SS: Tobacco carcinogens, their biomarkers and tobacco-induced cancer. Nat Rev Cancer. 3:733–744. 2003.PubMed/NCBI View Article : Google Scholar
22	Rabe KF and Watz H: Chronic obstructive pulmonary disease. Lancet. 389:1931–1940. 2017.PubMed/NCBI View Article : Google Scholar
23	Hogg JC and Timens W: The pathology of chronic obstructive pulmonary disease. Ann Rev Pathol. 4:435–459. 2009.PubMed/NCBI View Article : Google Scholar
24	Brandsma CA, Van den Berge M, Hackett TL, Brusselle G and Timens W: Recent advances in chronic obstructive pulmonary disease pathogenesis: From disease mechanisms to precision medicine. J Pathol. 250:624–635. 2020.PubMed/NCBI View Article : Google Scholar
25	Taylor JD: COPD and the response of the lung to tobacco smoke exposure. Pulm Pharmacol Ther. 23:376–383. 2010.PubMed/NCBI View Article : Google Scholar
26	Schupp JC, Adams TS, Cosme C Jr, Raredon MSB, Yuan Y, Omote N, Poli S, Chioccioli M, Rose KA, Manning EP, et al: Integrated single-cell atlas of endothelial cells of the human lung. Circulation. 144:286–302. 2021.PubMed/NCBI View Article : Google Scholar
27	Castro BM, Prieto M and Silva LC: Ceramide: A simple sphingolipid with unique biophysical properties. Prog Lipid Res. 54:53–67. 2014.PubMed/NCBI View Article : Google Scholar
28	Choi Y, Kim M, Kim SJ, Yoo HJ, Kim SH and Park HS: Metabolic shift favoring C18:0 ceramide accumulation in obese asthma. Allergy. 75:2858–2866. 2020.PubMed/NCBI View Article : Google Scholar
29	Ekroos K, Lavrynenko O, Titz B, Pater C, Hoeng J and Ivanov NV: Lipid-based biomarkers for CVD, COPD, and aging-A translational perspective. Prog Lipid Res. 78(101030)2020.PubMed/NCBI View Article : Google Scholar
30	McVey MJ, Weidenfeld S, Maishan M, Spring C, Kim M, Tabuchi A, Srbely V, Takabe-French A, Simmons S, Arenz C, et al: Platelet extracellular vesicles mediate transfusion-related acute lung injury by imbalancing the sphingolipid rheostat. Blood. 137:690–701. 2021.PubMed/NCBI View Article : Google Scholar
31	Tsurumaki H, Katano H, Sato K, Imai R, Niino S, Hirabayashi Y and Ichikawa S: WP1066, a small molecule inhibitor of the JAK/STAT3 pathway, inhibits ceramide glucosyltransferase activity. Biochem Biophys Res Commun. 491:265–270. 2017.PubMed/NCBI View Article : Google Scholar
32	Kurinna SM, Tsao CC, Nica AF, Jiffar T and Ruvolo PP: Ceramide promotes apoptosis in lung cancer-derived A549 cells by a mechanism involving c-Jun NH2-terminal kinase. Cancer Res. 64:7852–7856. 2004.PubMed/NCBI View Article : Google Scholar
33	Yeganeh B, Lee J, Bilodeau C, Lok I, Ermini L, Ackerley C, Caniggia I, Tibboel J, Kroon A and Post M: Acid sphingomyelinase inhibition attenuates cell death in mechanically ventilated newborn rat lung. Am J Respir Crit Care Med. 199:760–772. 2019.PubMed/NCBI View Article : Google Scholar
34	Kim SH, Singh MP, Sharma C and Kang SC: Fumonisin B1 actuates oxidative stress-associated colonic damage via apoptosis and autophagy activation in murine model. J Biochem Mol Toxicol. 22(e22161)2018.PubMed/NCBI View Article : Google Scholar
35	Rosenthal MD: Fatty acid metabolism of isolated mammalian cells. Prog Lipid Res. 26:87–124. 1987.PubMed/NCBI View Article : Google Scholar
36	Houten SM, Violante S, Ventura FV and Wanders RJA: The biochemistry and physiology of mitochondrial fatty acid β-oxidation and its genetic disorders. Ann Rev Physiol. 78:23–44. 2016.PubMed/NCBI View Article : Google Scholar
37	Han J, Qu H, Han M, Ding Y, Xie M, Hu J, Chen Y and Dong H: MSC-induced lncRNA AGAP2-AS1 promotes stemness and trastuzumab resistance through regulating CPT1 expression and fatty acid oxidation in breast cancer. Oncogene. 40:833–847. 2021.PubMed/NCBI View Article : Google Scholar
38	Dai J, Liang K, Zhao S, Jia W, Liu Y, Wu H, Lv J, Cao C, Chen T, Zhuang S, et al: Chemoproteomics reveals baicalin activates hepatic CPT1 to ameliorate diet-induced obesity and hepatic steatosis. Proc Natl Acad Sci USA. 115:E5896–E5905. 2018.PubMed/NCBI View Article : Google Scholar