Omentin-1 attenuates glucocorticoid-induced cardiac injury by phosphorylating GSK3β

in Journal of Molecular Endocrinology
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  • 1 Department of Anesthesiology, the First Affiliated Hospital of Wenzhou Medical University, Zhejiang Province, China
  • 2 Wenzhou Medical University, the First Affiliated Hospital of Zhejiang Province, China
  • 3 Department of Pain Treatment, the First Affiliated Hospital of Wenzhou Medical University, Zhejiang Province, China

Correspondence should be addressed to H Chen or J Zhang: chhfei@126.com or zhangjunkai@wzhospital.cn

Glucocorticoid excess often causes a variety of cardiovascular complications, including hypertension, atherosclerosis, and cardiac hypertrophy. To abrogate its cardiac side effects, it is necessary to fully disclose the pathophysiological role of glucocorticoid in cardiac remodelling. Previous clinical and experimental studies have found that omentin-1, one of the adipokines, has beneficial effects in cardiovascular diseases, and is closely associated with metabolic disorders. However, there is no evidence to address the potential role of omentin-1 in glucocorticoid excess-induced cardiac injuries. To uncover the links, the present study utilized rat model with glucocorticoid-induced cardiac injuries and clinical patients with abnormal cardiac function. Chronic administration of glucocorticoid excess reduced rat serum omentin-1 concentration, which closely correlated with cardiac functional parameters. Intravenous administration of adeno-associated virus encoding omentin-1 upregulated the circulating omentin-1 level and attenuated glucocorticoid excess-induced cardiac hypertrophy and functional disorders. Overexpression of omentin-1 also improved cardiac mitochondrial function, including the reduction of lipid deposits, induction of mitochondrial biogenesis, and enhanced mitochondrial activities. Mechanistically, omentin-1 phosphorylated and activated the GSK3β pathway in the heart. From a study of 28 patients with Cushing’s syndrome and 23 healthy subjects, the plasma level of glucocorticoid was negatively correlated with omentin-1, and was positively associated with cardiac ejection fraction and fractional shortening. Collectively, the present study provided a novel role of omentin-1 in glucocorticoid excess-induced cardiac injuries and found that the omentin-1/GSK3β pathway was a potential therapeutic target in combating the side effects of glucocorticoid.

Supplementary Materials

    • Figure S1. The distribution of omentin-1 in dexamethasone-treated rats.
    • Figure S2. Overexpression of omentin-1 suppressed dexamethasone-induced adipose hypertrophy in rats.

 

Society for Endocrinology

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  • Ahlbom E, Gogvadze V, Chen M, Celsi G & Ceccatelli S 2000 Prenatal exposure to high levels of glucocorticoids increases the susceptibility of cerebellar granule cells to oxidative stress-induced cell death. PNAS 97 1472614730. (https://doi.org/10.1073/pnas.260501697)

    • Search Google Scholar
    • Export Citation
  • Biscetti F, Nardella E, Bonadia N, Angelini F, Pitocco D, Santoliquido A, Filipponi M, Landolfi R & Flex A 2019 Association between plasma omentin-1 levels in type 2 diabetic patients and peripheral artery disease. Cardiovascular Diabetology 18 74. (https://doi.org/10.1186/s12933-019-0880-7)

    • Search Google Scholar
    • Export Citation
  • Biscetti F, Nardella E, Rando MM, Cecchini AL, Angelini F, Cina A, Iezzi R, Filipponi M, Santoliquido A & Pitocco D et al. 2020 Association between omentin-1 and major cardiovascular events after lower extremity endovascular revascularization in diabetic patients: a prospective cohort study. Cardiovascular Diabetology 19 170. (https://doi.org/10.1186/s12933-020-01151-z)

    • Search Google Scholar
    • Export Citation
  • Boscaro M, Barzon L, Fallo F & Sonino N 2001 Cushing’s syndrome. Lancet 357 783791. (https://doi.org/10.1016/S0140-6736(0004172-6)

  • Cimen AR, Cerit ET, Iyidir OT, Karakus R, Uyar BB, Toruner FB, Cakir N & Arslan M 2017 Serum Omentin-1 levels and endothelial dysfunction in obesity. Acta Endocrinology 13 138143. (https://doi.org/10.4183/aeb.2017.138)

    • Search Google Scholar
    • Export Citation
  • Cross DA, Alessi DR, Cohen P, Andjelkovich M & Hemmings BA 1995 Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378 785789. (https://doi.org/10.1038/378785a0)

    • Search Google Scholar
    • Export Citation
  • Du Y, Ji Q, Cai L, Huang F, Lai Y, Liu Y, Yu J, Han B, Zhu E & Zhang J et al. 2016 Association between omentin-1 expression in human epicardial adipose tissue and coronary atherosclerosis. Cardiovascular Diabetology 15 90. (https://doi.org/10.1186/s12933-016-0406-5)

    • Search Google Scholar
    • Export Citation
  • Elsaid NH, Sadik NA, Ahmed NR, Fayez SE & Mohammed NAE 2018 Serum omentin-1 levels in type 2 diabetic obese women in relation to glycemic control, insulin resistance and metabolic parameters. Journal of Clinical and Translational Endocrinology 13 1419. (https://doi.org/10.1016/j.jcte.2018.05.003)

    • Search Google Scholar
    • Export Citation
  • Fernandez-Ruiz I 2017 Imaging: mitochondria shine light on heart function. Nature Reviews: Cardiology 14 633. (https://doi.org/10.1038/nrcardio.2017.158)

    • Search Google Scholar
    • Export Citation
  • Gero D & Szabo C 2016 Glucocorticoids suppress mitochondrial oxidant production via upregulation of uncoupling protein 2 in hyperglycemic endothelial cells. PLoS ONE 11 e0154813. (https://doi.org/10.1371/journal.pone.0154813)

    • Search Google Scholar
    • Export Citation
  • Guder G, Bauersachs J, Frantz S, Weismann D, Allolio B, Ertl G, Angermann CE & Stork S 2007 Complementary and incremental mortality risk prediction by cortisol and aldosterone in chronic heart failure. Circulation 115 17541761. (https://doi.org/10.1161/CIRCULATIONAHA.106.653964)

    • Search Google Scholar
    • Export Citation
  • Iuchi T, Akaike M, Mitsui T, Ohshima Y, Shintani Y, Azuma H & Matsumoto T 2003 Glucocorticoid excess induces superoxide production in vascular endothelial cells and elicits vascular endothelial dysfunction. Circulation Research 92 8187. (https://doi.org/10.1161/01.res.0000050588.35034.3c)

    • Search Google Scholar
    • Export Citation
  • Joseph P, Leong D, McKee M, Anand SS, Schwalm JD, Teo K, Mente A & Yusuf S 2017 Reducing the global burden of cardiovascular disease, part 1: the epidemiology and risk factors. Circulation Research 121 677694. (https://doi.org/10.1161/CIRCRESAHA.117.308903)

    • Search Google Scholar
    • Export Citation
  • Jung CH, Jung SH, Kim BY, Kim CH, Kang SK & Mok JO 2015 Association of serum omentin levels with cardiac autonomic neuropathy in patients with type 2 diabetes mellitus: a hospital-based study. Cardiovascular Diabetology 14 140. (https://doi.org/10.1186/s12933-015-0303-3)

    • Search Google Scholar
    • Export Citation
  • Kang S, Louboutin JP, Datta P, Landel CP, Martinez D, Zervos AS, Strayer DS, Fernandes-Alnemri T & Alnemri ES 2013 Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging. Cell Death and Differentiation 20 259269. (https://doi.org/10.1038/cdd.2012.117)

    • Search Google Scholar
    • Export Citation
  • Kashani M, Eliasson A, Vernalis M, Costa L & Terhaar M 2013 Improving assessment of cardiovascular disease risk by using family history: an integrative literature review. Journal of Cardiovascular Nursing 28 E18E27. (https://doi.org/10.1097/JCN.0b013e318294b206)

    • Search Google Scholar
    • Export Citation
  • Kataoka Y, Shibata R, Ohashi K, Kambara T, Enomoto T, Uemura Y, Ogura Y, Yuasa D, Matsuo K & Nagata T et al. 2014 Omentin prevents myocardial ischemic injury through AMP-activated protein kinase- and Akt-dependent mechanisms. Journal of the American College of Cardiology 63 27222733. (https://doi.org/10.1016/j.jacc.2014.03.032)

    • Search Google Scholar
    • Export Citation
  • Kazama K, Okada M & Yamawaki H 2015 Adipocytokine, omentin inhibits doxorubicin-induced H9c2 cardiomyoblasts apoptosis through the inhibition of mitochondrial reactive oxygen species. Biochemical and Biophysical Research Communications 457 602607. (https://doi.org/10.1016/j.bbrc.2015.01.032)

    • Search Google Scholar
    • Export Citation
  • Kracun D, Klop M, Knirsch A, Petry A, Kanchev I, Chalupsky K, Wolf CM & Gorlach A 2020 NADPH oxidases and HIF1 promote cardiac dysfunction and pulmonary hypertension in response to glucocorticoid excess. Redox Biology 34 101536. (https://doi.org/10.1016/j.redox.2020.101536)

    • Search Google Scholar
    • Export Citation
  • Liu F, Fang S, Liu X, Li J, Wang X, Cui J, Chen T, Li Z, Yang F & Tian J et al. 2020 Omentin-1 protects against high glucose-induced endothelial dysfunction via the AMPK/PPARdelta Signalling pathway. Biochemical Pharmacology 174 113830. (https://doi.org/10.1016/j.bcp.2020.113830)

    • Search Google Scholar
    • Export Citation
  • Lucas T, Bonauer A & Dimmeler S 2018 RNA therapeutics in cardiovascular disease. Circulation Research 123 205220. (https://doi.org/10.1161/CIRCRESAHA.117.311311)

    • Search Google Scholar
    • Export Citation
  • Mann JI 2002 Diet and risk of coronary heart disease and type 2 diabetes. Lancet 360 783789. (https://doi.org/10.1016/s0140-6736(0209901-4)

    • Search Google Scholar
    • Export Citation
  • Muiesan ML, Lupia M, Salvetti M, Grigoletto C, Sonino N, Boscaro M, Rosei EA, Mantero F & Fallo F 2003 Left ventricular structural and functional characteristics in Cushing’s syndrome. Journal of the American College of Cardiology 41 22752279. (https://doi.org/10.1016/s0735-1097(0300493-5)

    • Search Google Scholar
    • Export Citation
  • Nie H, Pan Y & Zhou Y 2018 Exosomal microRNA-194 causes cardiac injury and mitochondrial dysfunction in obese mice. Biochemical and Biophysical Research Communications 503 31743179. (https://doi.org/10.1016/j.bbrc.2018.08.113)

    • Search Google Scholar
    • Export Citation
  • Pan Y, Zhu G, Wang Y, Cai L, Cai Y, Hu J, Li Y, Yan Y, Wang Z & Li X et al. 2013 Attenuation of high-glucose-induced inflammatory response by a novel curcumin derivative B06 contributes to its protection from diabetic pathogenic changes in rat kidney and heart. Journal of Nutritional Biochemistry 24 146155. (https://doi.org/10.1016/j.jnutbio.2012.03.012)

    • Search Google Scholar
    • Export Citation
  • Pan Y, Wang Y, Zhao Y, Peng K, Li W, Wang Y, Zhang J, Zhou S, Liu Q & Li X et al. 2014 Inhibition of JNK phosphorylation by a novel curcumin analog prevents high glucose-induced inflammation and apoptosis in cardiomyocytes and the development of diabetic cardiomyopathy. Diabetes 63 34973511. (https://doi.org/10.2337/db13-1577)

    • Search Google Scholar
    • Export Citation
  • Pan Y, Hui X, Hoo RLC, Ye D, Chan CYC, Feng T, Wang Y, Lam KSL & Xu A 2019 Adipocyte-secreted exosomal microRNA-34a inhibits M2 macrophage polarization to promote obesity-induced adipose inflammation. Journal of Clinical Investigation 129 834849. (https://doi.org/10.1172/JCI123069)

    • Search Google Scholar
    • Export Citation
  • Park DW, Jiang S, Liu Y, Siegal GP, Inoki K, Abraham E & Zmijewski JW 2014 GSK3beta-dependent inhibition of AMPK potentiates activation of neutrophils and macrophages and enhances severity of acute lung injury. American Journal of Physiology: Lung Cellular and Molecular Physiology 307 L735L745. (https://doi.org/10.1152/ajplung.00165.2014)

    • Search Google Scholar
    • Export Citation
  • Peng J, Zhou Y, Zhang Z, Wang Z, Gao L, Zhang X, Fang Z, Li G, Chen H & Yang H et al. 2018 The detrimental effects of glucocorticoids exposure during pregnancy on offspring’s cardiac functions mediated by hypermethylation of bone morphogenetic protein-4. Cell Death and Disease 9 834. (https://doi.org/10.1038/s41419-018-0841-1)

    • Search Google Scholar
    • Export Citation
  • Puthanveetil P & Rodrigues B 2013 Glucocorticoid excess induces accumulation of cardiac glycogen and triglyceride: suggested role for AMPK. Current Pharmaceutical Design 19 48184830. (https://doi.org/10.2174/13816128113199990340)

    • Search Google Scholar
    • Export Citation
  • Rao SS, Hu Y, Xie PL, Cao J, Wang ZX, Liu JH, Yin H, Huang J, Tan YJ & Luo J et al. 2018 Omentin-1 prevents inflammation-induced osteoporosis by downregulating the pro-inflammatory cytokines. Bone Research 6 9. (https://doi.org/10.1038/s41413-018-0012-0)

    • Search Google Scholar
    • Export Citation
  • Rathwa N, Patel R, Pramanik Palit S, Jadeja SD, Narwaria M, Ramachandran AV & Begum R 2019 Circulatory omentin-1 levels but not genetic variants influence the pathophysiology of type 2 diabetes. Cytokine 119 144151. (https://doi.org/10.1016/j.cyto.2019.03.011)

    • Search Google Scholar
    • Export Citation
  • Rose AJ & Herzig S 2013 Metabolic control through glucocorticoid hormones: an update. Molecular and Cellular Endocrinology 380 6578. (https://doi.org/10.1016/j.mce.2013.03.007)

    • Search Google Scholar
    • Export Citation
  • Roy SG, De P, Mukherjee D, Chander V, Konar A, Bandyopadhyay D & Bandyopadhyay A 2009 Excess of glucocorticoid induces cardiac dysfunction via activating angiotensin II pathway. Cellular Physiology and Biochemistry 24 110. (https://doi.org/10.1159/000227803)

    • Search Google Scholar
    • Export Citation
  • Sakota M, Tatebe S, Sugimura K, Aoki T, Yamamoto S, Sato H, Kikuchi N, Konno R, Terui Y & Satoh K et al. 2019 Successful management of acute congestive heart failure by emergent caesarean section followed by adrenalectomy in a pregnant woman with Cushing’s syndrome-induced cardiomyopathy. Internal Medicine 58 28192824. (https://doi.org/10.2169/internalmedicine.2427-18)

    • Search Google Scholar
    • Export Citation
  • Sato A, Suzuki H, Murakami M, Nakazato Y, Iwaita Y & Saruta T 1994 Glucocorticoid increases angiotensin II type 1 receptor and its gene expression. Hypertension 23 2530. (https://doi.org/10.1161/01.hyp.23.1.25)

    • Search Google Scholar
    • Export Citation
  • Shibata R, Ouchi N, Kikuchi R, Takahashi R, Takeshita K, Kataoka Y, Ohashi K, Ikeda N, Kihara S & Murohara T 2011 Circulating omentin is associated with coronary artery disease in men. Atherosclerosis 219 811814. (https://doi.org/10.1016/j.atherosclerosis.2011.08.017)

    • Search Google Scholar
    • Export Citation
  • Shibata R, Ouchi N, Takahashi R, Terakura Y, Ohashi K, Ikeda N, Higuchi A, Terasaki H, Kihara S & Murohara T 2012 Omentin as a novel biomarker of metabolic risk factors. Diabetology and Metabolic Syndrome 4 37. (https://doi.org/10.1186/1758-5996-4-37)

    • Search Google Scholar
    • Export Citation
  • Stejskal D, Vaclavik J, Smekal A, Svobodova G, Richterova R & Svestak M 2016 Omentin-1 levels in patients with premature coronary artery disease, metabolic syndrome and healthy controls. Short communication. Biomedical Papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia 160 219221. (https://doi.org/10.5507/bp.2016.019)

    • Search Google Scholar
    • Export Citation
  • Theeuwes WF, Gosker HR, Langen RCJ, Pansters NAM, Schols A & Remels AHV 2018 Inactivation of glycogen synthase kinase 3beta (GSK-3beta) enhances mitochondrial biogenesis during myogenesis. Biochimica et Biophysica Acta (BBA): Molecular Basis of Disease 1864 29132926.(https://doi.org/10.1016/j.bbadis.2018.06.002)

    • Search Google Scholar
    • Export Citation
  • Undi RB, Gutti U & Gutti RK 2017 LiCl regulates mitochondrial biogenesis during megakaryocyte development. Journal of Trace Elements in Medicine and Biology 39 193201. (https://doi.org/10.1016/j.jtemb.2016.10.003)

    • Search Google Scholar
    • Export Citation
  • Watanabe T, Watanabe-Kominato K, Takahashi Y, Kojima M & Watanabe R 2017 Adipose tissue-derived Omentin-1 function and regulation. Comprehensive Physiology 7 765781. (https://doi.org/10.1002/cphy.c160043)

    • Search Google Scholar
    • Export Citation
  • Whirledge S & DeFranco DB 2018 Glucocorticoid Signalling in health and disease: insights From tissue-specific GR knockout mice. Endocrinology 159 4664. (https://doi.org/10.1210/en.2017-00728)

    • Search Google Scholar
    • Export Citation
  • Whitehurst Jr RM, Zhang M, Bhattacharjee A & Li M 1999 Dexamethasone-induced hypertrophy in rat neonatal cardiac myocytes involves an elevated L-type Ca(2+)current. Journal of Molecular and Cellular Cardiology 31 15511558. (https://doi.org/10.1006/jmcc.1999.0990)

    • Search Google Scholar
    • Export Citation
  • WHO CVD Risk Chart Working Group 2019 World Health Organization cardiovascular disease risk charts: revised models to estimate risk in 21 global regions. Lancet: Global Health 7 e1332–e1345. (https://doi.org/10.1016/S2214-109X(1930318-3)

    • Search Google Scholar
    • Export Citation
  • Wong ND 2014 Epidemiological studies of CHD and the evolution of preventive cardiology. Nature Reviews: Cardiology 11 276289. (https://doi.org/10.1038/nrcardio.2014.26)

    • Search Google Scholar
    • Export Citation
  • Xu F, Li FX, Lin X, Zhong JY, Wu F, Shan SK, Tan CM, Yuan LQ & Liao XB 2019 Adipose tissue-derived omentin-1 attenuates arterial calcification via AMPK/Akt Signalling pathway. Aging 11 87608776. (https://doi.org/10.18632/aging.102251)

    • Search Google Scholar
    • Export Citation
  • Yoo HJ, Hwang SY, Hong HC, Choi HY, Yang SJ, Seo JA, Kim SG, Kim NH, Choi KM & Choi DS et al. 2011 Association of circulating omentin-1 level with arterial stiffness and carotid plaque in type 2 diabetes. Cardiovascular Diabetology 10 103. (https://doi.org/10.1186/1475-2840-10-103)

    • Search Google Scholar
    • Export Citation
  • Yu J, Yu B, He J, Zheng P, Mao X, Han G & Chen D 2014 Chronic glucocorticoid exposure-induced epididymal adiposity is associated with mitochondrial dysfunction in white adipose tissue of male C57BL/6J mice. PLoS ONE 9 e112628. (https://doi.org/10.1371/journal.pone.0112628)

    • Search Google Scholar
    • Export Citation
  • Zhu Y, Hu C, Du Y, Zhang J, Liu J, Cheng G, Han H & Zhao Y 2019 Time-dependent change in omentin-1 level correlated with early improvement of myocardial function in patients with first anterior ST-segment elevation myocardial infarction after primary percutaneous coronary intervention. Journal of Atherosclerosis and Thrombosis 26 856867. (https://doi.org/10.5551/jat.47043)

    • Search Google Scholar
    • Export Citation