LSD1 in beige adipocytes protects cardiomyocytes against oxygen and glucose deprivation

Document Type : Original Article

Authors

1 Department of Cardiac Surgery, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, 570311, People’s Republic of China

2 The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, People’s Republic of China

3 Department of Cardiovascular Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, People’s Republic of China

4 2 The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, People’s Republic of China

5 Department of Cardiovascular Surgery, Guangzhou Red Cross Hospital, Jinan University, 510235, People’s Republic of China

Abstract

Objective(s): Epicardial adipose tissue (EpAT) is known for its role in supporting the cardiomyocytes. Lysine-specific demethylase 1 (LSD1), a typical lysine demethylase, is an essential regulator for the maintenance of beige adipocytes. However, the effect of LSD1 in the adipogenic differentiation of beige adipocytes in EpAT, and its function on oxygen and glucose deprivation (OGD)-injured cardiomyocytes remain unclear.
Materials and Methods: Heart tissues from young mice and elder mice were collected for immunohistochemical staining. LSD1 in 3T3-L1 cells was knocked down by LSD1-shRNA lentivirus infection. The qRT-PCR, western blotting, and Oil Red O staining were employed to detect the adipogenic differentiation of 3T3-L1 cells and formation of beige adipocytes. The cardiomyocytes co-cultured with beige adipocytes were used for OGD treatment. Cell apoptosis was analyzed by flow cytometry. The lactate dehydrogenase (LDH) and superoxide dismutase (SOD) activity were analyzed using commercially available kits.
Results: The decrease of LSD1 was related to the age-dependent loss of beige adipocytes in mice EpAT. LSD1 knockdown inhibited the adipogenic differentiation of 3T3-L1 cells and formation of beige adipocytes. The down-regulation of LSD1 in 3T3-L1 cells decreased the protective effect of mature adipocytes on OGD-injured cardiomyocytes.
Conclusion: The decreased expression of LSD1 in mice EpAT was associated with age-dependent ablation of beige adipocytes. The protective effect of beige adipocytes on OGD-injured cardiomyocytes is reduced by knockdown of LSD1 in adipocytes. The present study provided exciting insights into establishing novel therapies against age-dependent cardiac diseases.

Keywords

References

1. Ansaldo AM, Montecucco F, Sahebkar A, Dallegri F, Carbone F. Epicardial adipose tissue and cardiovascular diseases. Int J Cardiol 2019; 278:254-260.
2. Talman AH, Psaltis PJ, Cameron JD, Meredith IT, Seneviratne SK, Wong DT. Epicardial adipose tissue: Far more than a fat depot. Cardiovasc Diagn Ther 2014; 4:416-429.
3. Chechi K, Richard D. Thermogenic potential and physiological relevance of human epicardial adipose tissue. Int J Obes Suppl 2015; 5:S28-34.
4. Rabkin SW. Epicardial fat: Properties, function and relationship to obesity. Obes Rev 2007; 8:253-261.
5. Rietdorf K, MacQueen H. Investigating interactions between epicardial adipose tissue and cardiac myocytes: what can we learn from different approaches? Br J Pharmacol 2017; 174:3542-3560.
6. Matloch Z, Kotulak T, Haluzik M. The role of epicardial adipose tissue in heart disease. Physiol Res 2016; 65:23-32.
7. Lage R, Moscoso I, Fernandez-Trasancos A, Cebro M, Couselo M, Fandino-Vaquero R, et al. Differential behaviour of epicardial adipose tissue-secretomes with high and low orosomucoid levels from patients with cardiovascular disease in H9C2 cells. Mol Cell Endocrinol 2015; 416:77-87.
8. Ishibashi J, Seale P. Medicine. Beige can be slimming. Science 2010; 328:1113-1114.
9. Himms-Hagen J, Melnyk A, Zingaretti MC, Ceresi E, Barbatelli G, Cinti S. Multilocular fat cells in WAT of CL-316243-treated rats derive directly from white adipocytes. Am J Physiol Cell Physiol 2000; 279:C670-681.
10. Cannon B, Nedergaard J. Brown adipose tissue: Function and physiological significance. Physiol Rev 2004; 84:277-359.
11. Rogers NH, Landa A, Park S, Smith RG. Aging leads to a programmed loss of brown adipocytes in murine subcutaneous white adipose tissue. Aging Cell 2012; 11:1074-1083.
12. Gu F, Lin Y, Wang Z, Wu X, Ye Z, Wang Y, et al. Biological roles of LSD1 beyond its demethylase activity. Cell Mol Life Sci 2020; 77:3341-3350.
13. Mulligan P, Yang F, Di Stefano L, Ji JY, Ouyang J, Nishikawa JL, et al. A SIRT1-LSD1 corepressor complex regulates Notch target gene expression and development. Mol Cell 2011; 42:689-699.
14. Duteil D, Tosic M, Schule R. Lsd1, a metabolic sensor of environment requirements that prevents adipose tissue from aging. Adipocyte 2017; 6:298-303.
15. Duteil D, Tosic M, Willmann D, Georgiadi A, Kanouni T, Schule R. Lsd1 prevents age-programed loss of beige adipocytes. Proc Natl Acad Sci U S A 2017; 114:5265-5270.
16. Lemecha M, Morino K, Imamura T, Iwasaki H, Ohashi N, Ida S, et al. MiR-494-3p regulates mitochondrial biogenesis and thermogenesis through PGC1-alpha signalling in beige adipocytes. Sci Rep 2018; 8:15096.
17. Fang X, Stroud MJ, Ouyang K, Fang L, Zhang J, Dalton ND, et al. Adipocyte-specific loss of PPARgamma attenuates cardiac hypertrophy. JCI Insight 2016; 1:e89908.
18. Bae IS, Kim SH. Expression and secretion of an atrial natriuretic peptide in beige-like 3T3-L1 adipocytes. Int J Mol Sci 2019; 20:6128.
19. Peng Y, Zhao JL, Peng ZY, Xu WF, Yu GL. Exosomal miR-25-3p from mesenchymal stem cells alleviates myocardial infarction by targeting pro-apoptotic proteins and EZH2. Cell Death Dis 2020; 11:317.
20. Dai S, Ye B, Zhong L, Chen Y, Hong G, Zhao G, et al. GSDMD Mediates LPS-Induced Septic Myocardial Dysfunction by Regulating ROS-dependent NLRP3 Inflammasome Activation. Front Cell Dev Biol 2021; 9:779432.
21. Balcerczyk A, Gajewska A, Macierzynska-Piotrowska E, Pawelczyk T, Bartosz G, Szemraj J. Enhanced antioxidant capacity and anti-ageing biomarkers after diet micronutrient supplementation. Molecules 2014; 19:14794-14808.
22. Sul HS. Minireview: Pref-1: Role in adipogenesis and mesenchymal cell fate. Mol Endocrinol 2009; 23:1717-1725.
23. Konno T, Sasaki K, Kobayashi K, Murata T. Indirubin promotes adipocyte differentiation and reduces lipid accumulation in 3T3L1 cells via peroxisome proliferatoractivated receptor gamma activation. Mol Med Rep 2020; 21:1552-1560.
24. Ikeda K, Maretich P, Kajimura S. The common and distinct features of brown and beige adipocytes. Trends Endocrinol Metab 2018; 29:191-200.
25. Wu J, Bostrom P, Sparks LM, Ye L, Choi JH, Giang AH, et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 2012; 150:366-376.
26. Sambeat A, Gulyaeva O, Dempersmier J, Tharp KM, Stahl A, Paul SM, et al. LSD1 interacts with Zfp516 to promote UCP1 transcription and brown fat program. Cell Rep 2016; 15:2536-2549.
27. Antonopoulos AS, Margaritis M, Verheule S, Recalde A, Sanna F, Herdman L, et al. Mutual regulation of epicardial adipose tissue and myocardial redox state by PPAR-gamma/adiponectin signalling. Circ Res 2016; 118:842-855.
28. Sacks HS, Fain JN, Holman B, Cheema P, Chary A, Parks F, et al. Uncoupling protein-1 and related messenger ribonucleic acids in human epicardial and other adipose tissues: epicardial fat functioning as brown fat. J Clin Endocrinol Metab 2009; 94:3611-3615.
29. Galmozzi A, Sonne SB, Altshuler-Keylin S, Hasegawa Y, Shinoda K, Luijten IHN, et al. ThermoMouse: an in vivo model to identify modulators of UCP1 expression in brown adipose tissue. Cell Rep 2014; 9:1584-1593.
30. Musri MM, Carmona MC, Hanzu FA, Kaliman P, Gomis R,  Parrizas M. Histone demethylase LSD1 regulates adipogenesis. J Biol Chem 2010; 285:30034-30041.
31. He Y, Ma N, Tang M, Jiang ZL, Liu H, Mei J. The differentiation of beige adipocyte in pericardial and epicardial adipose tissues induces atrial fibrillation development. Eur Rev Med Pharmacol Sci 2017; 21:4398-4405.
32. Thanassoulis G, Massaro JM, O’Donnell CJ, Hoffmann U, Levy D, Ellinor PT, et al. Pericardial fat is associated with prevalent atrial fibrillation: the Framingham Heart Study. Circ Arrhythm Electrophysiol 2010; 3:345-350.
33. Al Chekakie MO, Welles CC, Metoyer R, Ibrahim A, Shapira AR, Cytron J, et al. Pericardial fat is independently associated with human atrial fibrillation. J Am Coll Cardiol 2010; 56:784-788.
34. Zoni Berisso M, Landolina M, Ermini G, Parretti D, Zingarini GL, Degli Esposti L, et al. The cost of atrial fibrillation in Italy: a five-year analysis of healthcare expenditure in the general population. From the Italian Survey of Atrial Fibrillation Management (ISAF) study. Eur Rev Med Pharmacol Sci 2017; 21:175-183.
35. Seale P, Bjork B, Yang W, Kajimura S, Chin S, Kuang S, et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature 2008; 454:961-967.
36. Kajimura S, Saito M. A new era in brown adipose tissue biology: molecular control of brown fat development and energy homeostasis. Annu Rev Physiol 2014; 76:225-249.
37. Qian S, Huang H, Tang Q. Brown and beige fat: the metabolic function, induction, and therapeutic potential. Front Med 2015; 9:162-172.
38. Antoniades C, Antonopoulos AS, Tousoulis D, Stefanadis C. Adiponectin: From obesity to cardiovascular disease. Obes Rev 2009; 10:269-279.
39. Greulich S, Maxhera B, Vandenplas G, de Wiza DH, Smiris K, Mueller H, et al. Secretory products from epicardial adipose tissue of patients with type 2 diabetes mellitus induce cardiomyocyte dysfunction. Circulation 2012; 126:2324-2334.
40. Fan F, Duan Y, Yang F, Trexler C, Wang H, Huang L, et al. Deletion of heat shock protein 60 in adult mouse cardiomyocytes perturbs mitochondrial protein homeostasis and causes heart failure. Cell Death Differ 2020; 27:587-600.
41. Meng K, Jiao J, Zhu RR, Wang BY, Mao XB, Zhong YC, et al. The long noncoding RNA hotair regulates oxidative stress and cardiac myocyte apoptosis during ischemia-reperfusion injury. Oxid Med Cell Longev 2020; 2020:1645249.
42. Ekelof S, Jensen SE, Rosenberg J, Gogenur I. Reduced oxidative stress in STEMI patients treated by primary percutaneous coronary intervention and with antioxidant therapy: A systematic review. Cardiovasc Drugs Ther 2014; 28:173-181.
Iranian Journal of Basic Medical Sciences
Volume 26, Issue 1
January 2023
Pages 30-36

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