Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Internal Medicine Neurology Oncology Pediatrics Respiratory Medicine Surgery
Congress Coverage
2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting

Keynote Webinar | Spotlight on Diet and Diabetes

Watch on-demand

An expert-led symposium exploring the prevention and management of type 2 diabetes through dietary interventions. 
ADVANCED SEARCH
Log in
Top
Inflammation

22-09-2023 | Arterial Occlusive Disease | CORRESPONDENCE

Musclin Mitigates the Attachment of HUVECs to THP-1 Monocytes in Hyperlipidemic Conditions through PPARα/HO-1-Mediated Attenuation of Inflammation

Authors: Wonjun Cho, Heeseung Oh, Sung Woo Choi, A. M. Abd El-Aty, Fatma Yeşilyurt, Ji Hoon Jeong, Tae Woo Jung

Published in: Inflammation

Login to get access

Abstract

Musclin, a myokine, undergoes modulation during exercise and has demonstrated anti-inflammatory effects in cardiomyocytes and glomeruli. However, its role in atherosclerotic responses remains unclear. This study aimed to explore the impact of musclin on inflammatory responses and the interaction between endothelial cells and monocytes under hyperlipidemic conditions. The attachment levels of THP-1 monocytes on cultured HUVECs were examined. Inflammation and the expression of cell adhesion molecules were also evaluated. To explore the molecular mechanisms of musclin, PPARα or heme oxygenase 1 (HO-1) siRNA transfection was performed in HUVECs. The results revealed that treatment with recombinant musclin effectively suppressed the attachment of palmitate-induced HUVECs to THP-1 cells and reduced the expression of cell adhesion proteins (ICAM-1, VCAM-1, and E-selectin) in HUVECs. Furthermore, musclin treatment ameliorated the expression of inflammation markers (phosphorylated NFκB and IκB) in both HUVECs and THP-1 monocytes, as well as the release of TNFα and MCP-1 from HUVECs and THP-1 monocytes. Notably, musclin treatment augmented the expression levels of PPARα and HO-1. However, when PPARα or HO-1 siRNA was employed, the beneficial effects of musclin on inflammation, cell attachment, and adhesion molecule expression were abolished. These findings indicate that musclin exerts anti-inflammatory effects via the PPARα/HO-1 pathway, thereby mitigating the interaction between endothelial cells and monocytes. This study provides evidence supporting the important role of musclin in ameliorating obesity-related arteriosclerosis and highlights its potential as a therapeutic agent for treating arteriosclerosis.

Graphical Abstract

Appendix
Available only for authorised users
Literature
1.
Powell-Wiley, T.M., P. Poirier, L.E. Burke, J.P. Despres, P. Gordon-Larsen, C.J. Lavie, S.A. Lear, C.E. Ndumele, I.J. Neeland, P. Sanders, M.P. St-Onge, American Heart Association Council on Lifestyle and Cardiometabolic Health, Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology, Council on Epidemiology and Prevention, and Stroke Council. 2021. Obesity and cardiovascular disease: a scientific statement from the American Heart Association. Circulation 143: e984–e1010. PubMedPubMedCentralCrossRef
2.
Hai, A.A., S. Iftikhar, S. Latif, F. Herekar, S. Javed, and M.J. Patel. 2019. Prevalence of metabolic syndrome in overweight and obese patients and their measurement of neck circumference: a cross-sectional study. Cureus 11: e6114. PubMedPubMedCentral
3.
Reardon, C.A., A. Lingaraju, K.Q. Schoenfelt, G. Zhou, C. Cui, H. Jacobs-El, I. Babenko, A. Hoofnagle, D. Czyz, H. Shuman, T. Vaisar, and L. Becker. 2018. Obesity and insulin resistance promote atherosclerosis through an IFNgamma-regulated macrophage protein network. Cell Reports 23: 3021–3030. PubMedCrossRef
4.
Doehner, W., J. Schenkel, S.D. Anker, J. Springer, and H.J. Audebert. 2013. Overweight and obesity are associated with improved survival, functional outcome, and stroke recurrence after acute stroke or transient ischaemic attack: observations from the TEMPiS trial. European Heart Journal 34: 268–277. PubMedCrossRef
5.
Din-Dzietham, R., Y. Liu, M.V. Bielo, and F. Shamsa. 2007. High blood pressure trends in children and adolescents in national surveys, 1963 to 2002. Circulation 116: 1488–1496. PubMedCrossRef
6.
Bogers, R.P., W.J. Bemelmans, R.T. Hoogenveen, H.C. Boshuizen, M. Woodward, P. Knekt, R.M. van Dam, F.B. Hu, T.L. Visscher, A. Menotti, R.J. Thorpe Jr., K. Jamrozik, S. Calling, B.H. Strand, M.J. Shipley, and BMI-CHD Collaboration Investigators. 2007. Association of overweight with increased risk of coronary heart disease partly independent of blood pressure and cholesterol levels: a meta-analysis of 21 cohort studies including more than 300 000 persons. Archives of Internal Medicine 167: 1720–1728. PubMedCrossRef
7.
Henning, R.J. 2021. Obesity and obesity-induced inflammatory disease contribute to atherosclerosis: a review of the pathophysiology and treatment of obesity. American Journal of Cardiovascular Diseases 11: 504–529.
8.
Simonetto, C., S. Rospleszcz, M. Heier, C. Meisinger, A. Peters, and J.C. Kaiser. 2021. Simulating the dynamics of atherosclerosis to the incidence of myocardial infarction, applied to the KORA population. Statistics in Medicine 40: 3299–3312. PubMedCrossRef
9.
Soehnlein, O., and P. Libby. 2021. Targeting inflammation in atherosclerosis - from experimental insights to the clinic. Nature Reviews Drug Discovery 20: 589–610. PubMedPubMedCentralCrossRef
10.
Libby, P., and G.K. Hansson. 2015. Inflammation and immunity in diseases of the arterial tree: players and layers. Circulation Research 116: 307–311. PubMedPubMedCentralCrossRef
11.
Collins, R.G., R. Velji, N.V. Guevara, M.J. Hicks, L. Chan, and A.L. Beaudet. 2000. P-Selectin or intercellular adhesion molecule (ICAM)-1 deficiency substantially protects against atherosclerosis in apolipoprotein E-deficient mice. Journal of Experimental Medicine 191: 189–194. PubMedPubMedCentralCrossRef
12.
Shih, P.T., M.L. Brennan, D.K. Vora, M.C. Territo, D. Strahl, M.J. Elices, A.J. Lusis, and J.A. Berliner. 1999. Blocking very late antigen-4 integrin decreases leukocyte entry and fatty streak formation in mice fed an atherogenic diet. Circulation Research 84: 345–351. PubMedCrossRef
13.
Subbotina, E., A. Sierra, Z. Zhu, Z. Gao, S.R. Koganti, S. Reyes, E. Stepniak, S.A. Walsh, M.R. Acevedo, C.M. Perez-Terzic, D.M. Hodgson-Zingman, and L.V. Zingman. 2015. Musclin is an activity-stimulated myokine that enhances physical endurance. Proceedings of the National Academy of Sciences 112: 16042–16047. CrossRef
14.
Nishizawa, H., M. Matsuda, Y. Yamada, K. Kawai, E. Suzuki, M. Makishima, T. Kitamura, and I. Shimomura. 2004. Musclin, a novel skeletal muscle-derived secretory factor. Journal of Biological Chemistry 279: 19391–19395. PubMedCrossRef
15.
Sanchez, Y.L., M. Yepes-Calderon, L. Valbuena, A.F. Milan, M.C. Trillos-Almanza, S. Granados, M. Pena, M. Estrada-Castrillon, J.C. Aristizabal, R. Narvez-Sanchez, J. Gallo-Villegas, and J.C. Calderon. 2021. Musclin is related to insulin resistance and body composition, but not to body mass index or cardiorespiratory capacity in adults. Endocrinology and Metabolism 36: 1055–1068. PubMedPubMedCentralCrossRef
16.
Gallo-Villegas, J., L.A. Castro-Valencia, L. Perez, D. Restrepo, O. Guerrero, S. Cardona, Y.L. Sanchez, M. Yepes-Calderon, L.H. Valbuena, M. Pena, A.F. Milan, M.C. Trillos-Almanza, S. Granados, J.C. Aristizabal, M. Estrada-Castrillon, R. Narvaez-Sanchez, J. Osorio, D.C. Aguirre-Acevedo, and J.C. Calderon. 2022. Efficacy of high-intensity interval- or continuous aerobic-training on insulin resistance and muscle function in adults with metabolic syndrome: a clinical trial. European Journal of Applied Physiology 122: 331–344. PubMedCrossRef
17.
Shimomura, M., N. Horii, S. Fujie, K. Inoue, N. Hasegawa, K. Iemitsu, M. Uchida, and M. Iemitsu. 2021. Decreased muscle-derived musclin by chronic resistance exercise is associated with improved insulin resistance in rats with type 2 diabetes. Physiological Reports 9: e14823. PubMedPubMedCentralCrossRef
18.
Liu, Y., X. Huo, X.F. Pang, Z.H. Zong, X. Meng, and G.L. Liu. 2008. Musclin inhibits insulin activation of Akt/protein kinase B in rat skeletal muscle. Journal of International Medical Research 36: 496–504. PubMedCrossRef
19.
Kattih, B., D.C. Carstens, F. Boeckling, T. Rasper, G. Pergola, S. Dimmeler, M. Vasa-Nicotera, A.M. Zeiher, and S. Mas-Peiro. 2022. Low circulating musclin is associated with adverse prognosis in patients undergoing transcatheter aortic valve implantation at low-intermediate risk. Journal of the American Heart Association 11: e022792. PubMedPubMedCentralCrossRef
20.
Cho, W., S.W. Choi, H. Oh, F. Baygutalp, A.M. Abd El-Aty, J.H. Jeong, J.H. Song, Y.K. Shin, and T.W. Jung. 2023. Musclin attenuates lipid deposition in hepatocytes through SIRT7/autophagy-mediated suppression of ER stress. Biochemical and Biophysical Research Communications 658: 62–68. PubMedCrossRef
21.
Choi, S.W., H. Oh, S.Y. Park, W. Cho, A.M. Abd El-Aty, A. Hacimuftuoglu, J.H. Jeong, and T.W. Jung. 2023. Myokine musclin alleviates lipid accumulation in 3T3-L1 adipocytes through PKA/p38-mediated upregulation of lipolysis and suppression of lipogenesis. Biochemical and Biophysical Research Communications 642: 113–117. PubMedCrossRef
22.
Hu, C., X. Zhang, N. Zhang, W.Y. Wei, L.L. Li, Z.G. Ma, and Q.Z. Tang. 2020. Osteocrin attenuates inflammation, oxidative stress, apoptosis, and cardiac dysfunction in doxorubicin-induced cardiotoxicity. Clinical and Translational Medicine 10: e124. PubMedPubMedCentralCrossRef
23.
Handa, T., K.P. Mori, A. Ishii, S. Ohno, Y. Kanai, H. Watanabe-Takano, A. Yasoda, T. Kuwabara, N. Takahashi, N. Mochizuki, M. Mukoyama, M. Yanagita, and H. Yokoi. 2021. Osteocrin ameliorates adriamycin nephropathy via p38 mitogen-activated protein kinase inhibition. Science and Reports 11: 21835. CrossRef
24.
Sandfort, V., S. Lai, M.A. Ahlman, M. Mallek, S. Liu, C.T. Sibley, E.B. Turkbey, J.A. Lima, and D.A. Bluemke. 2016. Obesity is associated with progression of atherosclerosis during statin treatment. Journal of the American Heart Association 5: e003621. PubMedPubMedCentralCrossRef
25.
Spagnoli, L.G., E. Bonanno, G. Sangiorgi, and A. Mauriello. 2007. Role of inflammation in atherosclerosis. Journal of Nuclear Medicine 48: 1800–1815. PubMedCrossRef
26.
27.
Durante, W. 2011. Protective role of heme oxygenase-1 against inflammation in atherosclerosis. Frontiers in Bioscience (Landmark Edition) 16: 2372–2388. PubMedCrossRef
28.
Kronke, G., A. Kadl, E. Ikonomu, S. Bluml, A. Furnkranz, I.J. Sarembock, V.N. Bochkov, M. Exner, B.R. Binder, and N. Leitinger. 2007. Expression of heme oxygenase-1 in human vascular cells is regulated by peroxisome proliferator-activated receptors. Arteriosclerosis, Thrombosis, and Vascular Biology 27: 1276–1282. PubMedCrossRef
29.
30.
Pawlak, M., P. Lefebvre, and B. Staels. 2015. Molecular mechanism of PPARalpha action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. Journal of Hepatology 62: 720–733. PubMedCrossRef
31.
32.
Frick, M.H., O. Elo, K. Haapa, O.P. Heinonen, P. Heinsalmi, P. Helo, J.K. Huttunen, P. Kaitaniemi, P. Koskinen, V. Manninen, et al. 1987. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. New England Journal of Medicine 317: 1237–1245. PubMedCrossRef
33.
Cao, H., G. Wen, and H. Li. 2014. Role of peroxisome proliferator-activated receptor alpha in atherosclerosis. Molecular Medicine Reports 9: 1755–1760. PubMedCrossRef
34.
Han, C.Y., T. Chiba, J.S. Campbell, N. Fausto, M. Chaisson, G. Orasanu, J. Plutzky, and A. Chait. 2006. Reciprocal and coordinate regulation of serum amyloid A versus apolipoprotein A-I and paraoxonase-1 by inflammation in murine hepatocytes. Arteriosclerosis, Thrombosis, and Vascular Biology 26: 1806–1813. PubMedCrossRef
35.
Ziouzenkova, O., S. Perrey, L. Asatryan, J. Hwang, K.L. MacNaul, D.E. Moller, D.J. Rader, A. Sevanian, R. Zechner, G. Hoefler, and J. Plutzky. 2003. Lipolysis of triglyceride-rich lipoproteins generates PPAR ligands: evidence for an antiinflammatory role for lipoprotein lipase. Proceedings of the National Academy of Sciences 100: 2730–2735. CrossRef
36.
Pae, H.O., Y. Son, N.H. Kim, H.J. Jeong, K.C. Chang, and H.T. Chung. 2010. Role of heme oxygenase in preserving vascular bioactive NO. Nitric Oxide 23: 251–257. PubMedCrossRef
37.
Abraham, N.G., P.L. Tsenovoy, J. McClung, and G.S. Drummond. 2008. Heme oxygenase: a target gene for anti-diabetic and obesity. Current Pharmaceutical Design 14: 412–421. PubMedCrossRef
38.
Chen, X., S.Y. Wei, J.S. Li, Q.F. Zhang, Y.X. Wang, S.L. Zhao, J. Yu, C. Wang, Y. Qin, Q.J. Wei, G.X. Lv, and B. Li. 2016. Overexpression of heme oxygenase-1 prevents renal interstitial inflammation and fibrosis induced by unilateral ureter obstruction. PLoS ONE 11: e0147084. PubMedPubMedCentralCrossRef
39.
40.
Kwon, C.H., J.L. Sun, M.J. Kim, A.M. Abd El-Aty, J.H. Jeong, and T.W. Jung. 2020. Clinically confirmed DEL-1 as a myokine attenuates lipid-induced inflammation and insulin resistance in 3T3-L1 adipocytes via AMPK/HO-1- pathway. Adipocyte 9: 576–586. PubMedPubMedCentralCrossRef
41.
Yet, S.F., M.D. Layne, X. Liu, Y.H. Chen, B. Ith, N.E. Sibinga, and M.A. Perrella. 2003. Absence of heme oxygenase-1 exacerbates atherosclerotic lesion formation and vascular remodeling. The FASEB Journal 17: 1759–1761. PubMedCrossRef
42.
Li, Y.X., K.C. Cheng, A. Asakawa, I. Kato, Y. Sato, H. Amitani, N. Kawamura, J.T. Cheng, A. Inui. 2013. Role of musclin in the pathogenesis of hypertension in rat. PLoS One 8: e72004.
Metadata
Title
Musclin Mitigates the Attachment of HUVECs to THP-1 Monocytes in Hyperlipidemic Conditions through PPARα/HO-1-Mediated Attenuation of Inflammation
Authors
Wonjun Cho
Heeseung Oh
Sung Woo Choi
A. M. Abd El-Aty
Fatma Yeşilyurt
Ji Hoon Jeong
Tae Woo Jung
Publication date
22-09-2023
Publisher
Springer US
Published in
Inflammation
Print ISSN: 0360-3997
Electronic ISSN: 1573-2576
DOI
https://doi.org/10.1007/s10753-023-01904-4
Webinar | 08-11-2023 | 18:00 (CET)

Keynote Webinar | Spotlight on Diet and Diabetes

Watch now

An expert-led symposium exploring the prevention and management of type 2 diabetes through dietary interventions. Highlights include discussion of the recent EASD guidelines, therapeutic diets, food types and processing, plus psychological factors that influence patient success, and the drivers of healthy eating and diabetes control.
Prof. Mike Lean
Prof. Falko Sniehotta
Image Credits