Abstract
Cardiac inflammation contributes to heart failure (HF) induced by isoproterenol (ISO) through activating β-adrenergic receptors (β-AR). Recent evidence shows that myeloid differentiation factor 2 (MD2), a key protein in endotoxin-induced inflammation, mediates inflammatory heart diseases. In this study, we investigated the role of MD2 in ISO-β-AR-induced heart injuries and HF. Mice were infused with ISO (30 mg·kg−1·d−1) via osmotic mini-pumps for 2 weeks. We showed that MD2 in cardiomyocytes and cardiac macrophages was significantly increased and activated in the heart tissues of ISO-challenged mice. Either MD2 knockout or administration of MD2 inhibitor L6H21 (10 mg/kg every 2 days, i.g.) could prevent mouse hearts from ISO-induced inflammation, remodelling and dysfunction. Bone marrow transplantation study revealed that both cardiomyocyte MD2 and bone marrow-derived macrophage MD2 contributed to ISO-induced cardiac inflammation and injuries. In ISO-treated H9c2 cardiomyocyte-like cells, neonatal rat primary cardiomyocytes and primary mouse peritoneal macrophages, MD2 knockout or pre-treatment with L6H21 (10 μM) alleviated ISO-induced inflammatory responses, and the conditioned medium from ISO-challenged macrophages promoted the hypertrophy and fibrosis in cardiomyocytes and fibroblasts. We demonstrated that ISO induced MD2 activation in cardiomyocytes via β1-AR-cAMP-PKA-ROS signalling axis, and induced inflammatory responses in macrophages via β2-AR-cAMP-PKA-ROS axis. This study identifies MD2 as a key inflammatory mediator and a promising therapeutic target for ISO-induced heart failure.
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References
Benjamin EJ, Muntner P, Alonso A, Bittencourt MS, Callaway CW, Carson AP, et al. Heart disease and stroke statistics-2019 update: a report from the American Heart association. Circulation. 2019;139:e56–e528.
Cohn JN, Levine TB, Olivari MT, Garberg V, Lura D, Francis GS, et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med. 1984;311:819–23.
El-Armouche A, Eschenhagen T. Beta-adrenergic stimulation and myocardial function in the failing heart. Heart Fail Rev. 2009;14:225–41.
Murray DR, Prabhu SD, Chandrasekar B. Chronic beta-adrenergic stimulation induces myocardial proinflammatory cytokine expression. Circulation. 2000;101:2338–41.
Szabo-Fresnais N, Lefebvre F, Germain A, Fischmeister R, Pomérance M. A new regulation of IL-6 production in adult cardiomyocytes by beta-adrenergic and IL-1 beta receptors and induction of cellular hypertrophy by IL-6 trans-signalling. Cell Signal. 2010;22:1143–52.
Tsutamoto T, Hisanaga T, Wada A, Maeda K, Ohnishi M, Fukai D, et al. Interleukin-6 spillover in the peripheral circulation increases with the severity of heart failure, and the high plasma level of interleukin-6 is an important prognostic predictor in patients with congestive heart failure. J Am Coll Cardiol. 1998;31:391–8.
Toyoda S, Haruyama A, Inami S, Arikawa T, Saito F, Watanabe R, et al. Effects of carvedilol vs bisoprolol on inflammation and oxidative stress in patients with chronic heart failure. J Cardiol. 2020;75:140–7.
Woo AY, Xiao RP. β-Adrenergic receptor subtype signaling in heart: from bench to bedside. Acta Pharmacol Sin. 2012;33:335–41.
Kossack M, Hein S, Juergensen L, Siragusa M, Benz A, Katus HA, et al. Induction of cardiac dysfunction in developing and adult zebrafish by chronic isoproterenol stimulation. J Mol Cell Cardiol. 2017;108:95–105.
Meeran MFN, Azimullah S, Adeghate E, Ojha S. Nootkatone attenuates myocardial oxidative damage, inflammation, and apoptosis in isoproterenol-induced myocardial infarction in rats. Phytomedicine. 2021;84:153405.
Park SH, Kim ND, Jung JK, Lee CK, Han SB, Kim Y. Myeloid differentiation 2 as a therapeutic target of inflammatory disorders. Pharmacol Ther. 2012;133:291–8.
Park BS, Lee JO. Recognition of lipopolysaccharide pattern by TLR4 complexes. Exp Mol Med. 2013;45:e66.
Han J, Zou C, Mei L, Zhang Y, Qian Y, You S, et al. MD2 mediates angiotensin II-induced cardiac inflammation and remodelling via directly binding to Ang II and activating TLR4/NF-κB signaling pathway. Basic Res Cardiol. 2017;112:9.
Chen T, Huang W, Qian J, Luo W, Shan P, Cai Y, et al. Macrophage-derived myeloid differentiation protein 2 plays an essential role in ox-LDL-induced inflammation and atherosclerosis. EBioMedicine. 2020;53:102706.
Riad A, Gross S, Witte J, Feldtmann R, Wagner KB, Reinke Y, et al. MD-2 is a new predictive biomarker in dilated cardiomyopathy and exerts direct effects in isolated cardiomyocytes. Int J Cardiol. 2018;270:278–86.
Wang Y, Qian Y, Fang Q, Zhong P, Li W, Wang L, et al. Author Correction: Saturated palmitic acid induces myocardial inflammatory injuries through direct binding to TLR4 accessory protein MD2. Nat Commun. 2018;9:16185.
Wang Y, Luo W, Han J, Khan ZA, Fang Q, Jin Y, et al. MD2 activation by direct AGE interaction drives inflammatory diabetic cardiomyopathy. Nat Commun. 2020;11:2148.
Wang Y, Shan X, Chen G, Jiang L, Wang Z, Fang Q, et al. MD-2 as the target of a novel small molecule, L6H21, in the attenuation of LPS-induced inflammatory response and sepsis. Br J Pharmacol. 2015;172:4391–405.
Li C, Zhao M, Xiao L, Wei H, Wen Z, Hu D, et al. Prognostic value of elevated levels of plasma N-Acetylneuraminic acid in patients with heart failure. Circ Heart Fail. 2021;14:e008459.
Zhao H, Yang H, Geng C, Chen Y, Pang J, Shu T, et al. Role of IgE-FcεR1 in pathological cardiac remodelling and dysfunction. Circulation. 2021;143:1014–30.
Ye S, Luo W, Khan ZA, Wu G, Xuan L, Shan P, et al. Celastrol attenuates angiotensin II-induced cardiac remodelling by targeting STAT3. Circ Res. 2020;126:1007–23.
Dasu MR, Devaraj S, Zhao L, Hwang DH, Jialal I. High glucose induces toll-like receptor expression in human monocytes: mechanism of activation. Diabetes. 2008;57:3090–8.
Adzika GK, Machuki JO, Shang W, Hou H, Ma T, Wu L, et al. Pathological cardiac hypertrophy: the synergy of adenylyl cyclases inhibition in cardiac and immune cells during chronic catecholamine stress. J Mol Med (Berl). 2019;97:897–907.
Scanzano A, Cosentino M. Adrenergic regulation of innate immunity: a review. Front Pharmacol. 2015;6:171.
Xiao H, Li H, Wang JJ, Zhang JS, Shen J, An XB, et al. IL-18 cleavage triggers cardiac inflammation and fibrosis upon β-adrenergic insult. Eur Heart J. 2018;39:60–9.
Tanner MA, Maitz CA, Grisanti LA. Immune cell β(2)-adrenergic receptors contribute to the development of heart failure. Am J Physiol Heart Circ Physiol. 2021;321:H633–49.
Corbi G, Conti V, Russomanno G, Longobardi G, Furgi G, Filippelli A, et al. Adrenergic signaling and oxidative stress: a role for sirtuins? Front Physiol. 2013;4:324.
Hertz AL, Bender AT, Smith KC, Gilchrist M, Amieux PS, Aderem A, et al. Elevated cyclic AMP and PDE4 inhibition induce chemokine expression in human monocyte-derived macrophages. Proc Natl Acad Sci USA 2009;106:21978–83.
Cao N, Wang JJ, Wu JM, Xu WL, Wang R, Chen XD, et al. Glibenclamide alleviates β adrenergic receptor activation-induced cardiac inflammation. Acta Pharmacol Sin. 2022;43:1243–50.
Karam S, Margaria JP, Bourcier A, Mika D, Varin A, Bedioune I, et al. Cardiac overexpression of PDE4B blunts β-adrenergic response and maladaptive remodelling in heart failure. Circulation. 2020;142:161–74.
Xu Q, Dalic A, Fang L, Kiriazis H, Ritchie RH, Sim K, et al. Myocardial oxidative stress contributes to transgenic β2-adrenoceptor activation-induced cardiomyopathy and heart failure. Br J Pharmacol. 2011;162:1012–28.
Remondino A, Kwon SH, Communal C, Pimentel DR, Sawyer DB, Singh K, et al. Beta-adrenergic receptor-stimulated apoptosis in cardiac myocytes is mediated by reactive oxygen species/c-Jun NH2-terminal kinase-dependent activation of the mitochondrial pathway. Circ Res. 2003;92:136–8.
Theccanat T, Philip JL, Razzaque AM, Ludmer N, Li J, Xu X, et al. Regulation of cellular oxidative stress and apoptosis by G protein-coupled receptor kinase-2; The role of NADPH oxidase 4. Cell Signal. 2016;28:190–203.
Chen H, Song Z, Ying S, Yang X, Wu W, Tan Q, et al. Myeloid differentiation protein 2 induced retinal ischemia reperfusion injury via upregulation of ROS through a TLR4-NOX4 pathway. Toxicol Lett. 2018;282:109–20.
Koenig A, Buskiewicz-Koenig IA. Redox activation of mitochondrial DAMPs and the metabolic consequences for development of autoimmunity. Antioxid Redox Signal. 2022;36:441–61.
Gong T, Liu L, Jiang W, Zhou R. DAMP-sensing receptors in sterile inflammation and inflammatory diseases. Nat Rev Immunol. 2020;20:95–112.
Sun JH, Yang HX, Yao TT, Li Y, Ruan L, Xu GR, et al. Gentianella acuta prevents acute myocardial infarction induced by isoproterenol in rats via inhibition of galectin-3/TLR4/MyD88/NF-кB inflammatory signalling. Inflammopharmacology. 2021;29:205–19.
Bai C, Ren Y, Huang J, Zhang Y, Li L, Du G. High-mobility group Box-1 regulates acute myocardial ischemia-induced injury through the toll-like receptor 4-related pathway. Int J Clin Exp Pathol. 2017;10:8344–52.
Yang H, Wang H, Andersson U. Targeting inflammation driven by HMGB1. Front Immunol. 2020;11:484.
de Oliveira AA, Faustino J, de Lima ME, Menezes R, Nunes KP. Unveiling the interplay between the TLR4/MD2 complex and HSP70 in the human cardiovascular system: a computational approach. Int J Mol Sci. 2019;20:3121.
Frieler RA, Mortensen RM. Immune cell and other noncardiomyocyte regulation of cardiac hypertrophy and remodelling. Circulation. 2015;131:1019–30.
Qian J, Liang S, Wang Q, Xu J, Huang W, Wu G, et al. Toll-like receptor-2 in cardiomyocytes and macrophages mediates isoproterenol-induced cardiac inflammation and remodelling. FASEB J. 2023;37:e22740.
Stapel B, Kohlhaas M, Ricke-Hoch M, Haghikia A, Erschow S, Knuuti J, et al. Low STAT3 expression sensitizes to toxic effects of β-adrenergic receptor stimulation in peripartum cardiomyopathy. Eur Heart J. 2017;38:349–61.
Porter KE, Turner NA. Cardiac fibroblasts: at the heart of myocardial remodelling. Pharmacol Ther. 2009;123:255–78.
She G, Hou MC, Zhang Y, Zhang Y, Wang Y, Wang HF, et al. Gal-3 (Galectin-3) and K(Ca)3.1 mediate heterogeneous cell coupling and myocardial fibrogenesis driven by βAR (β-adrenoceptor) activation. Hypertension. 2020;75:393–404.
Benjamin IJ, Jalil JE, Tan LB, Cho K, Weber KT, Clark WA. Isoproterenol-induced myocardial fibrosis in relation to myocyte necrosis. Circ Res. 1989;65:657–70.
Tanner MA, Thomas TP, Maitz CA, Grisanti LA. β2-Adrenergic receptors increase cardiac fibroblast proliferation through the Gαs/ERK1/2-dependent secretion of interleukin-6. Int J Mol Sci. 2020;21:8507.
Aránguiz-Urroz P, Canales J, Copaja M, Troncoso R, Vicencio JM, Carrillo C, et al. Beta(2)-adrenergic receptor regulates cardiac fibroblast autophagy and collagen degradation. Biochim Biophys Acta. 2011;1812:23–31.
Wei M, Li Z, Xiao L, Yang Z. Effects of ROS-relative NF-κB signaling on high glucose-induced TLR4 and MCP-1 expression in podocyte injury. Mol Immunol. 2015;68:261–71.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (82271347 to GJW) and Wenzhou City Research Project (ZY2020016 to GJW).
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This work was carried out in collaboration among all authors. GL and GJW designed experiments. JFQ, SQL, QYW, JCX performed experiments. JFQ and WL analyzed the data collection and analysis. GL, JFQ and GJW analyzed the data and wrote the manuscript. GL and WJH revised the manuscript. All the authors edited and approved the manuscript.
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Qian, Jf., Liang, Sq., Wang, Qy. et al. Isoproterenol induces MD2 activation by β-AR-cAMP-PKA-ROS signalling axis in cardiomyocytes and macrophages drives inflammatory heart failure. Acta Pharmacol Sin 45, 531–544 (2024). https://doi.org/10.1038/s41401-023-01179-3
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DOI: https://doi.org/10.1038/s41401-023-01179-3