Abstract
Upon chronic stress, β-adrenergic receptor activation induces cardiac fibrosis and leads to heart failure. The small molecule compound IMM-H007 has demonstrated protective effects in cardiovascular diseases via activation of AMP-activated protein kinase (AMPK). This study aimed to investigate IMM-H007 effects on cardiac fibrosis induced by β-adrenergic receptor activation. Because adenosine analogs also exert AMPK-independent effects, we assessed AMPK-dependent and -independent IMM-H007 effects in murine models of cardiac fibrosis. Continual subcutaneous injection of isoprenaline for 7 days caused cardiac fibrosis and cardiac dysfunction in mice in vivo. IMM-H007 attenuated isoprenaline-induced cardiac fibrosis, diastolic dysfunction, α-smooth muscle actin expression, and collagen I deposition in both wild-type and AMPKα2−/− mice. Moreover, IMM-H007 inhibited transforming growth factor β1 (TGFβ1) expression in wild-type, but not AMPKα2−/− mice. By contrast, IMM-H007 inhibited Smad2/3 signaling downstream of TGFβ1 in both wild-type and AMPKα2−/− mice. Surface plasmon resonance and molecular docking experiments showed that IMM-H007 directly interacts with TGFβ1, inhibits its binding to TGFβ type II receptors, and downregulates the Smad2/3 signaling pathway downstream of TGFβ1. These findings suggest that IMM-H007 inhibits isoprenaline-induced cardiac fibrosis via both AMPKα2-dependent and -independent mechanisms. IMM-H007 may be useful as a novel TGFβ1 antagonist.
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References
Travers JG, Kamal FA, Robbins J, Yutzey KE, Blaxall BC. Cardiac fibrosis: the fibroblast awakens. Circ Res. 2016;118:1021–40.
Kong P, Christia P, Frangogiannis NG. The pathogenesis of cardiac fibrosis. Cell Mol Life Sci. 2014;71:549–74.
Berk BC, Fujiwara K, Lehoux S. ECM remodeling in hypertensive heart disease. J Clin Invest. 2007;117:568–75.
Weber KT, Sun Y, Bhattacharya SK, Ahokas RA, Gerling IC. Myofibroblast-mediated mechanisms of pathological remodelling of the heart. Nat Rev Cardiol. 2013;10:15–26.
Fu Y, Xiao H, Zhang Y. Beta-adrenoceptor signaling pathways mediate cardiac pathological remodeling. Front Biosci (Elite Ed). 2012;4:1625–37.
Anand IS, Fisher LD, Chiang YT, Latini R, Masson S, Maggioni AP, et al. Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HeFT). Circulation. 2003;107:1278–83.
Dixon R, Gourzis J, McDermott D, Fujitaki J, Dewland P, Gruber H. AICA-riboside: safety, tolerance, and pharmacokinetics of a novel adenosine-regulating agent. J Clin Pharmacol. 1991;31:342–7.
Sun Y, Lian Z, Jiang C, Wang Y, Zhu H. Beneficial metabolic effects of 2’,3’,5’-tri-acetyl-N6-(3-hydroxylaniline) adenosine in the liver and plasma of hyperlipidemic hamsters. PLoS One. 2012;7:e32115.
Lian Z, Li Y, Gao J, Qu K, Li J, Hao L, et al. A novel AMPK activator, WS070117, improves lipid metabolism discords in hamsters and HepG2 cells. Lipids Health Dis. 2011;10:67.
Huang L, Fan B, Ma A, Shaul PW, Zhu H. Inhibition of ABCA1 protein degradation promotes HDL cholesterol efflux capacity and RCT and reduces atherosclerosis in mice. J Lipid Res. 2015;56:986–97.
Chen B, Li J, Zhu H. AMP-activated protein kinase attenuates oxLDL uptake in macrophages through PP2A/NF-κB/LOX-1 pathway. Vasc Pharmacol. 2016;85:1–10.
Wang MJ, Peng XY, Lian ZQ, Zhu HB. The cordycepin derivative IMM-H007 improves endothelial dysfunction by suppressing vascular inflammation and promoting AMPK-dependent eNOS activation in high-fat diet-fed ApoE knockout mice. Eur J Pharmacol. 2019;852:167–78.
Guigas B, Bertrand L, Taleux N, Foretz M, Wiernsperger N, Vertommen D, et al. 5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside and metformin inhibit hepatic glucose phosphorylation by an AMP-activated protein kinase-independent effect on glucokinase translocation. Diabetes. 2006;55:865–74.
Foretz M, Hébrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G, et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest. 2010;120:2355–69.
Mia MM, Cibi DM, Ghani SA, Singh A, Tee N, Sivakumar V, et al. Loss of Yap/Taz in cardiac fibroblasts attenuates adverse remodeling and improves cardiac function. Cardiovasc Res. 2021. https://doi.org/10.1093/cvr/cvab205.
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.
Wu D, Lei H, Wang JY, Zhang CL, Feng H, Fu FY, et al. CTRP3 attenuates post-infarct cardiac fibrosis by targeting Smad3 activation and inhibiting myofibroblast differentiation. J Mol Med. 2015;93:1311–25.
Mishra R, Cool BL, Laderoute KR, Foretz M, Viollet B, Simonson MS. AMP-activated protein kinase inhibits transforming growth factor-β-induced Smad3-dependent transcription and myofibroblast transdifferentiation. J Biol Chem. 2008;283:10461–9.
Fujita K, Maeda N, Sonoda M, Ohashi K, Hibuse T, Nishizawa H, et al. Adiponectin protects against angiotensin II-induced cardiac fibrosis through activation of PPAR-α. Arterioscler Thromb Vasc Biol. 2008;28:863–70.
Ge W, Zhang W, Gao R, Li B, Zhu H, Wang J. IMM-H007 improves heart function via reducing cardiac fibrosis. Eur J Pharmacol. 2019;857:172442.
Xiao H, Zhang J, Xu Z, Feng Y, Zhang M, Liu J, et al. Metformin is a novel suppressor for transforming growth factor (TGF)-β1. Sci Rep. 2016;6:28597.
Feng Y, Wang S, Zhang Y, Xiao H. Metformin attenuates renal fibrosis in both AMPKα2-dependent and independent manners. Clin Exp Pharmacol Physiol. 2017;44:648–55.
Xiao H, Ma X, Feng W, Fu Y, Lu Z, Xu M, et al. Metformin attenuates cardiac fibrosis by inhibiting the TGFβ1–Smad3 signalling pathway. Cardiovasc Res. 2010;87:504–13.
Lin CC, Yeh HH, Huang WL, Yan JJ, Lai WW, Su WP, et al. Metformin enhances cisplatin cytotoxicity by suppressing signal transducer and activator of transcription-3 activity independently of the liver kinase B1-AMP-activated protein kinase pathway. Am J Respir Cell Mol Biol. 2013;49:241–50.
Stapleton D, Mitchelhill KI, Gao G, Widmer J, Michell BJ, Teh T, et al. Mammalian AMP-activated protein kinase subfamily. J Biol Chem. 1996;271:611–4.
Qiu S, Liu T, Piao C, Wang Y, Wang K, Zhou Y, et al. AMPKα2 knockout enhances tumour inflammation through exacerbated liver injury and energy deprivation-associated AMPKα1 activation. J Cell Mol Med. 2019;23:1687–97.
Noppe G, Dufeys C, Buchlin P, Marquet N, Castanares-Zapatero D, Balteau M, et al. Reduced scar maturation and contractility lead to exaggerated left ventricular dilation after myocardial infarction in mice lacking AMPKα1. J Mol Cell Cardiol. 2014;74:32–43.
Dufeys C, Daskalopoulos EP, Castanares-Zapatero D, Conway SJ, Ginion A, Bouzin C, et al. AMPKα1 deletion in myofibroblasts exacerbates post-myocardial infarction fibrosis by a connexin 43 mechanism. Basic Res Cardiol. 2021;116:10.
Duvnjak M, Tomasic V, Gomercic M, Smircic Duvnjak L, Barsic N, Lerotic I. Therapy of nonalcoholic fatty liver disease: current status. J Physiol Pharmacol. 2009;60:57–66.
Bottinger EP, Bitzer M. TGF-β signaling in renal disease. J Am Soc Nephrol. 2002;13:2600–10.
Chapman HA. Epithelial-mesenchymal interactions in pulmonary fibrosis. Annu Rev Physiol. 2011;73:413–35.
Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-β family signalling. Nature. 2003;425:577–84.
Acknowledgements
This work was supported by the National Key R&D Program (grant numbers 2020YFC2004704 to HX), Natural Science Foundation of China (grant numbers 82030072 to HX, 81830009 to YYZ, and 82070235 to EDD), the Beijing Municipal Natural Science Foundation (grant number 7191013 to EDD), Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences (2021RU003 to EDD), and the Key Clinical Projects of Peking University Third Hospital [BYSYZD2019022 to HX].
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HX, EDD, YYZ, and HBZ conceived the project and designed the study. HBZ provided the drug. SXW, YNF, SF, and MZ performed the experiments. SXW, JMW, and WLX analyzed the data. SXW, JMW, and YNF wrote the manuscript.
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Wang, Sx., Feng, Yn., Feng, S. et al. IMM-H007 attenuates isoprenaline-induced cardiac fibrosis through targeting TGFβ1 signaling pathway. Acta Pharmacol Sin 43, 2542–2549 (2022). https://doi.org/10.1038/s41401-022-00899-2
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DOI: https://doi.org/10.1038/s41401-022-00899-2
