The Potential Role of Interleukin-37 in Diabetic Cardiomyopathy
Received Date: Oct 18, 2017 / Accepted Date: Nov 13, 2017 / Published Date: Nov 20, 2017
Cardiovascular disease is the major reason of death in patients with Type 2 diabetes mellitus (T2DM) and accounts for up to 80% of associated mortality . Diabetic cardiomyopathy (DCM), initially reported by Rubler and colleagues from diabetic patients who died of heart failure without cardiovascular disease in 1972, is characterized by lipid accumulation in cardiomyocytes, fetal gene reactivation, and cardiac hypertrophy, which together confers a 2-3 fold increased risk of heart failure [2,3]. The pathophysiological mechanisms underlying the characteristic features of diabetic cardiomyopathy are poorly understood, although multiple factors including hyperglycemia, hyperinsulinemia and hyperlipidemia mediated lipid accumulation, apoptosis, ROS stress, inflammation, as well as fibrosis, remodeling of cardiomyocytes are implicated . IL-37 plays an important role in both innate and adaptive immunity, which has been reported to be associated with various kinds of inflammatory and autoimmune diseases [5,6]. Recent studies also showed that IL-37 played a role in tumorigenesis, angiogenesis, furthermore in autophagy and insulin sensitivity [7-10]. In this paper, we mainly point out the widespread potentially regulatory functions of IL-37 in DCM.
Impaired insulin metabolic signaling causes stiffness and diastolic dysfunction of the heart, which is a critical pathophysiological abnormality associated with DCM. Lipid accumulation (lipotoxicity) can directly impede myocyte metabolism and contractility [1,4]. Ballak et al. reported that the glucose tolerance and insulin sensitivity were significantly improved in IL-37 mice after 16 weeks of HFD feeding, meanwhile this type of mice showed reduced plasma levels of cholesterol, free fatty acids and triglycerides, also implying a role in the regulation of cholesterol homeostasis . Mice treated with IL-37 could induce remarkable metabolic changes with higher levels of muscle AMP-activated protein kinase (AMPK), greater rates of oxygen consumption, and increased oxidative phosphorylation, and showed a further 326% increase in exercise performance . Above metabolic regulation role of IL-37 is closely associated with the regulation of AMPK activation, which is known to play a primary role in metabolic reprogramming, and functions as an important protective action against the development of pathogenesis of many cardiovascular diseases including DCM . Therefore, IL-37 may be a target to mitigate the detrimental effects of diabetes mellitus in DCM by regulating the insulin sensitivity and lipid homeostasis.
The production of reactive oxygen species (ROS) has been shown to be increased in patients with diabetes . Metabolic disturbances induce subcellular minor inflammation response in the heart. The innate immune system comprising of neutrophils, dendritic cells, macrophages, mast cells, and eosinophils also induces chronic metabolic inflammation, which is proved to implicate in the development of DCM2. Classical TLR4 and downstream signaling pathway, NLRP3 inflammasome, and regulated inflammatory cytokines such as TNF-α, IL-6, IL-1β and IL-18 are considered to mediate the interaction between cardiac cells and immune cells, which are closely related with the ROS stress, cardiomyocytes apoptosis, and the fibrosis course in the pathophysiology of DCM2, . In addition, study also reported that adaptive immunity also involved in the DCM, as was shown that depletion of Treg cells aggravates myocardial fibrosis . Besides, we found that IL-37 could protect cardiomyocytes from apoptosis and myocardial ROS stress under I/R condition , whether it also plays a role in hyperglycemia induced cardiomyocytes apoptosis remains further investigation. Moreover, studies have shown that elevated oxidative stress and inflammation might produce substrates that fuel autophagic protein degradation, and the accumulation of oxidized and nitrated proteins and lipids also indicate an abrogated autophagic processes in DCM, which in consistent with a blunted mammalian target of rapamycin (mTOR) pathway and a reduced activity of AMPK in DCM12, . As showed by the study of Li et al. that IL-37 promoted autophagy in SMMC-7721 and Huh-7 cells via inhibition of the PI3K/AKT/mTOR signaling pathway7, IL-37 may also ameliorate the pathological processes in DCM by inducing autophagy. From the researches done so far, the anti-inflammatory characteristics of IL-37 may make it a potential therapeutic target for DCM.
IL-37 mainly acts through a Smad3-dependent mechanism, and Smad3-TGFβ pathway was associated with fibrosis ; but study showed that AAV/human Smad3 delivery observed an antiatherosclerosis therapeutic effect without the expected undesirable effect of TGFβ1-associated fibrosis . Besides, IL-37 was also found to be involved in the pathogenesis of proliferative diabetic retinopathy . In summary, based on the discussion above, IL-37 may play a protective role in DCM, yet studies are still needed to investigate the exact role of IL-37 in DCM in order to provide new evidence for clinical practice.
This work was supported by National Natural Science Foundation of China (81470496, 81573710), National Natural Science Foundation of Shanghai (17ZR1403700) and Chinese Medicine Science Foundation of Shanghai Health and Family Planning Committee (2014JZ006A).
Conflict of Interest
- Lorenzo-Almoros A, Tunon J, Orejas M, Cortes M, Egido J, et al. (2017) Diagnostic approaches for diabetic cardiomyopathy. Cardiovasc Diabetol 16: 28.
- Mishra PK, Ying W, Nandi SS, Bandyopadhyay GK, Patel KK, et al. (2017) Diabetic Cardiomyopathy: An Immunometabolic Perspective. Front Endocrinol (Lausanne) 8: 72.
- Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, et al. (1972) New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol 30: 595-602.
- Tate M, Grieve DJ, Ritchie RH (2017) Are targeted therapies for diabetic cardiomyopathy on the horizon? Clin Sci (Lond) 131: 897-915.
- Zhuang X, Wu B, Li J, Shi H, Jin B, et al. (2017) The emerging role of interleukin-37 in cardiovascular diseases. Immun Inflamm Dis 5: 373-379.
- Nold MF, Nold-Petry CA, Zepp JA, Palmer BE, Bufler P, et al. (2010) IL-37 is a fundamental inhibitor of innate immunity. Nat Immunol 11: 1014-1022.
- Li TT, Zhu D, Mou T, Guo Z, Pu JL, et al. (2017) IL-37 induces autophagy in hepatocellular carcinoma cells by inhibiting the PI3K/AKT/mTOR pathway. Mol Immunol 87: 132-140.
- Yang T, Lin Q, Zhao M, Hu Y, Yu Y, et al. (2015) IL-37 Is a Novel Proangiogenic Factor of Developmental and Pathological Angiogenesis. Arterioscler Thromb Vasc Biol 35: 2638-46.
- Ballak DB, van Diepen JA, Moschen AR, Jansen HJ, Hijmans A, et al. (2014) IL-37 protects against obesity-induced inflammation and insulin resistance. Nat Commun 5: 4711.
- Ding VA, Zhu Z, Xiao H, Wakefield MR, Bai Q, et al. (2016) The role of IL-37 in cancer. Med Oncol 33: 68.
- Cavalli G, Justice JN, Boyle KE, D'Alessandro A, Eisenmesser EZ, et al. (2017) Interleukin 37 reverses the metabolic cost of inflammation, increases oxidative respiration, and improves exercise tolerance. Proc Natl Acad Sci USA 114: 2313-2318.
- Daskalopoulos EP, Dufeys C, Beauloye C, et al. (2016) AMPK in Cardiovascular Diseases. EXS 107: 179-201.
- Faria A, Persaud SJ (2017) Cardiac oxidative stress in diabetes: Mechanisms and therapeutic potential. Pharmacol Ther 172: 50-62.
- Fuentes-Antras J, Ioan AM, Tunon J, Egido J, Lorenzo O (2014) Activation of toll-like receptors and inflammasome complexes in the diabetic cardiomyopathy-associated inflammation. Int J Endocrinol 2014: 847827.
- Meng X, Yang J, Dong M, Zhang K, Tu E, et al. (2016) Regulatory T cells in cardiovascular diseases. Nat Rev Cardiol 13: 167-179.
- Wu B, Meng K, Ji Q, Cheng M, Yu K, et al. (2014) Interleukin-37 ameliorates myocardial ischaemia/reperfusion injury in mice. Clin Exp Immunol 176: 438-51.
- Varga ZV, Giricz Z, Liaudet L, Hasko G, Ferdinandy P, et al. (2015) Interplay of oxidative, nitrosative/nitrative stress, inflammation, cell death and autophagy in diabetic cardiomyopathy. Biochim Biophys Acta 1852: 232-42.
- Xu S, Liu AC, Gotlieb AI (2010) Common pathogenic features of atherosclerosis and calcific aortic stenosis: role of transforming growth factor-beta. Cardiovasc Pathol 19: 236-47.
- Zhu H, Cao M, Figueroa JA, Cobos E, Uretsky BF, et al. (2014) AAV2/8-hSMAD3 gene delivery attenuates aortic atherogenesis, enhances Th2 response without fibrosis, in LDLR-KO mice on high cholesterol diet. J Transl Med 12: 252.
- Zhao M, Hu Y, Yu Y, Lin Q, Yang J, et al. (2016) Involvement of IL-37 in the Pathogenesis of Proliferative Diabetic Retinopathy. Invest Ophthalmol Vis Sci 57: 2955-62.
Citation: Wu B, Li J (2017) The Potential Role of Interleukin-37 in Diabetic Cardiomyopathy. J Clin Cell Immunol 8: 529. Doi: 10.4172/2155-9899.1000529
Copyright: ©2017 Wu B, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Select your language of interest to view the total content in your interested language
Share This Article
September 17-18, 2018 San Diego, USA
December 05-06, 2018 Chicago, USA
- Total views: 714
- [From(publication date): 0-2017 - Aug 20, 2018]
- Breakdown by view type
- HTML page views: 678
- PDF downloads: 36