Sympathetic stress is prevalent in cardiovascular diseases. Sympathetic overactivation under strong acute stresses triggers acute cardiovascular events including myocardial infarction (MI), sudden cardiac death, and stress cardiomyopathy. α1-ARs and β-ARs, two dominant subtypes of adrenergic receptors in the heart, play a significant role in the physiological and pathologic regulation of these processes. However, little is known about the functional similarities and differences between α1- and β-ARs activated temporal responses in stress-induced cardiac pathology. In this work, we systematically compared the cardiac temporal genome-wide profiles of acute α1-AR and β-AR activation in the mice model by integrating transcriptome and proteome. We found that α1- and β-AR activations induced sustained and transient inflammatory gene expression, respectively. Particularly, the overactivation of α1-AR but not β-AR led to neutrophil infiltration at one day, which was closely associated with the up-regulation of chemokines, activation of NF-κB pathway, and sustained inflammatory response. Furthermore, there are more metabolic disorders under α1-AR overactivation compared with β-AR overactivation. These findings provide a new therapeutic strategy that, besides using β-blocker as soon as possible, blocking α1-AR within one day should also be considered in the treatment of acute stress-associated cardiovascular diseases.
This is a preview of subscription content, access via your institution
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Scott-Solomon E, Boehm E, Kuruvilla R. The sympathetic nervous system in development and disease. Nat Rev Neurosci. 2021;22:685–702.
Hering D, Lachowska K, Schlaich M. Role of the sympathetic nervous system in stress-mediated cardiovascular disease. Curr Hypertens Rep. 2015;17:80.
O’Connell TD, Jensen BC, Baker AJ, Simpson PC. Cardiac alpha1-adrenergic receptors: novel aspects of expression, signaling mechanisms, physiologic function, and clinical importance. Pharmacol Rev. 2014;66:308–33.
Kivimäki M, Steptoe A. Effects of stress on the development and progression of cardiovascular disease. Nat Rev Cardiol. 2018;15:215–29.
Jensen BC, OʼConnell TD, Simpson PC. Alpha-1-adrenergic receptors in heart failure: the adaptive arm of the cardiac response to chronic catecholamine stimulation. J Cardiovasc Pharmacol. 2014;63:291–301.
Wachter SB, Gilbert EM. Beta-adrenergic receptors, from their discovery and characterization through their manipulation to beneficial clinical application. Cardiology. 2012;122:104–12.
Baker AJ. Adrenergic signaling in heart failure: a balance of toxic and protective effects. Pflug Arch. 2014;466:1139–50.
do Vale GT, Ceron CS, Gonzaga NA, Simplicio JA, Padovan JC. Three generations of β-blockers: history, class differences and clinical applicability. Curr Hypertens Rev. 2019;15:22–31.
Wright JM, Musini VM, Gill R. First-line drugs for hypertension. Cochrane Database Syst Rev. 2018;4:Cd001841.
Myagmar BE, Flynn JM, Cowley PM, Swigart PM, Montgomery MD, Thai K, et al. Adrenergic receptors in individual ventricular myocytes: the Beta-1 and Alpha-1B are in all cells, the Alpha-1A is in a subpopulation, and the Beta-2 and Beta-3 are mostly absent. Circ Res. 2017;120:1103–15.
Motiejunaite J, Amar L, Vidal-Petiot E. Adrenergic receptors and cardiovascular effects of catecholamines. Ann Endocrinol. 2021;82:193–7.
Vonderlin N, Siebermair J, Kaya E, Köhler M, Rassaf T, Wakili R. Critical inflammatory mechanisms underlying arrhythmias. Herz. 2019;44:121–9.
Ong SB, Hernández-Reséndiz S, Crespo-Avilan GE, Mukhametshina RT, Kwek XY, Cabrera-Fuentes HA, et al. Inflammation following acute myocardial infarction: Multiple players, dynamic roles, and novel therapeutic opportunities. Pharmacol Ther. 2018;186:73–87.
Murphy SP, Kakkar R, McCarthy CP, Januzzi JL Jr. Inflammation in heart failure: JACC state-of-the-art review. J Am Coll Cardiol. 2020;75:1324–40.
Singh T, Khan H, Gamble DT, Scally C, Newby DE, Dawson D. Takotsubo syndrome: pathophysiology, emerging concepts, and clinical implications. Circulation. 2022;145:1002–19.
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.
Xin JZ, Wu JM, Hu GM, Gu HJ, Feng YN, Wang SX, et al. α(1)-AR overactivation induces cardiac inflammation through NLRP3 inflammasome activation. Acta Pharmacol Sin. 2020;41:311–8.
Kim D, Langmead B, Salzberg SL. HISAT: a fast spliced aligner with low memory requirements. Nat Methods. 2015;12:357–60.
Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.
Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS: A J Integr Biol. 2012;16:284–7.
Cox J, Hein MY, Luber CA, Paron I, Nagaraj N, Mann M. Accurate proteome-wide label-free quantification by delayed normalization and maximal peptide ratio extraction, termed MaxLFQ. Mol Cell Proteom. 2014;13:2513–26.
Bruderer R, Bernhardt OM, Gandhi T, Miladinović SM, Cheng LY, Messner S, et al. Extending the limits of quantitative proteome profiling with data-independent acquisition and application to acetaminophen-treated three-dimensional liver microtissues. Mol Cell Proteom. 2015;14:1400–10.
Tie L, Xiao H, Wu DL, Yang Y, Wang P. A brief guide to good practices in pharmacological experiments: Western blotting. Acta Pharmacol Sin. 2021;42:1015–7.
Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019;47:D607–d13.
Xin JZ, Wu JM, Hu GM, Gu HJ, Feng YN, Wang SX, et al. α1-AR overactivation induces cardiac inflammation through NLRP3 inflammasome activation. Acta Pharmacol Sin. 2020;41:311–8.
Lafuse WP, Wozniak DJ, Rajaram MVS. Role of cardiac macrophages on cardiac inflammation, fibrosis and tissue repair. Cells. 2020;10:51.
De Larco JE, Wuertz BR, Furcht LT. The potential role of neutrophils in promoting the metastatic phenotype of tumors releasing interleukin-8. Clin Cancer Res. 2004;10:4895–900.
Rosales C. Neutrophil: a cell with many roles in inflammation or several cell types. Front Physiol. 2018;9:113.
Charo IF, Ransohoff RM. The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med. 2006;354:610–21.
Capucetti A, Albano F, Bonecchi R. Multiple roles for chemokines in neutrophil biology. Front Immunol. 2020;11:1259.
Hu N, Westra J, Rutgers A, Doornbos-Van der Meer B, Huitema MG, Stegeman CA, et al. Decreased CXCR1 and CXCR2 expression on neutrophils in anti-neutrophil cytoplasmic autoantibody-associated vasculitides potentially increases neutrophil adhesion and impairs migration. Arthritis Res Ther. 2011;13:R201.
Nolan KF, Strong V, Soler D, Fairchild PJ, Cobbold SP, Croxton R, et al. IL-10-conditioned dendritic cells, decommissioned for recruitment of adaptive immunity, elicit innate inflammatory gene products in response to danger signals. J Immunol. 2004;172:2201.
Das T, Chen Z, Hendriks RW, Kool M. A20/tumor necrosis factor α-induced protein 3 in immune cells controls development of autoinflammation and autoimmunity: lessons from mouse models. Front Immunol. 2018;9:104.
Regan-Komito D, Valaris S, Kapellos TS, Recio C, Taylor L, Greaves DR, et al. Absence of the non-signalling chemerin receptor CCRL2 exacerbates acute inflammatory responses in vivo. Front Immunol. 2017;8:1621.
Mandeville I, Aubin J, LeBlanc M, Lalancette-Hébert M, Janelle MF, Tremblay GM, et al. Impact of the loss of Hoxa5 function on lung alveogenesis. Am J Pathol. 2006;169:1312–27.
Becker F, Potepalov S, Shehzahdi R, Bernas M, Witte M, Abreo F, et al. Downregulation of FoxC2 increased susceptibility to experimental colitis: influence of lymphatic drainage function? Inflamm Bowel Dis. 2015;21:1282–96.
George T, Bell M, Chakraborty M, Siderovski DP, Giembycz MA, Newton R. Protective roles for RGS2 in a mouse model of house dust mite-induced airway inflammation. PLoS One. 2017;12:e0170269.
Immler R, Simon SI, Sperandio M. Calcium signalling and related ion channels in neutrophil recruitment and function. Eur J Clin Invest. 2018;48:e12964.
Béguin P, Nagashima K, Mahalakshmi RN, Vigot R, Matsunaga A, Miki T, et al. BARP suppresses voltage-gated calcium channel activity and Ca2+-evoked exocytosis. J Cell Biol. 2014;205:233–49.
Liu T, Zhang L, Joo D, Sun SC. NF-κB signaling in inflammation. Signal Transduct Target Ther. 2017;2:17023.
Maguire O, O’Loughlin K, Minderman H. Simultaneous assessment of NF-κB/p65 phosphorylation and nuclear localization using imaging flow cytometry. J Immunol Methods. 2015;423:3–11.
Martínez-Reyes I, Chandel NS. Mitochondrial TCA cycle metabolites control physiology and disease. Nat Commun. 2020;11:102.
Liu Y, Beyer A, Aebersold R. On the dependency of cellular protein levels on mRNA abundance. Cell. 2016;165:535–50.
Dewenter M, Pan J, Knödler L, Tzschöckel N, Henrich J, Cordero J, et al. Chronic isoprenaline/phenylephrine vs. exclusive isoprenaline stimulation in mice: critical contribution of alpha(1)-adrenoceptors to early cardiac stress responses. Basic Res Cardiol. 2022;117:15.
Butterfield TA, Best TM, Merrick MA. The dual roles of neutrophils and macrophages in inflammation: a critical balance between tissue damage and repair. J Athl Train. 2006;41:457–65.
Watanabe S, Alexander M, Misharin AV, Budinger GRS. The role of macrophages in the resolution of inflammation. J Clin Invest. 2019;129:2619–28.
Kim Y, Nurakhayev S, Nurkesh A, Zharkinbekov Z, Saparov A. Macrophage polarization in cardiac tissue repair following myocardial infarction. Int J Mol Sci. 2021;22:2715.
Tang KM, Wang GR, Lu P, Karas RH, Aronovitz M, Heximer SP, et al. Regulator of G-protein signaling-2 mediates vascular smooth muscle relaxation and blood pressure. Nat Med. 2003;9:1506–12.
Schioppa T, Sozio F, Barbazza I, Scutera S, Bosisio D, Sozzani S, et al. Molecular basis for CCRL2 regulation of leukocyte migration. Front Cell Dev Biol. 2020;8:615031.
Sjögren B, Parra S, Atkins KB, Karaj B, Neubig RR. Digoxin-mediated upregulation of RGS2 protein protects against cardiac injury. J Pharmacol Exp Ther. 2016;357:311–9.
Li HM, Li KY, Xing Y, Tang XX, Yang DM, Dai XM, et al. Phenylephrine attenuated sepsis-induced cardiac inflammation and mitochondrial injury through an effect on the PI3K/Akt signaling pathway. J Cardiovasc Pharmacol. 2019;73:186–94.
Li PL, Liu H, Chen GP, Li L, Shi HJ, Nie HY, et al. STEAP3 (six-transmembrane epithelial antigen of prostate 3) inhibits pathological cardiac hypertrophy. Hypertension. 2020;76:1219–30.
Kumar S, Wang G, Liu W, Ding W, Dong M, Zheng N, et al. Hypoxia-induced mitogenic factor promotes cardiac hypertrophy via calcium-dependent and hypoxia-inducible factor-1α mechanisms. Hypertension. 2018;72:331–42.
Yamamura S, Izumiya Y, Araki S, Nakamura T, Kimura Y, Hanatani S, et al. Cardiomyocyte Sirt (Sirtuin) 7 ameliorates stress-induced cardiac hypertrophy by interacting with and deacetylating GATA4. Hypertension. 2020;75:98–108.
Soehnlein O, Lindbom L, Weber C. Mechanisms underlying neutrophil-mediated monocyte recruitment. Blood. 2009;114:4613–23.
Silvestre-Roig C, Braster Q, Ortega-Gomez A, Soehnlein O. Neutrophils as regulators of cardiovascular inflammation. Nat Rev Cardiol. 2020;17:327–40.
Schiattarella GG, Rodolico D, Hill JA. Metabolic inflammation in heart failure with preserved ejection fraction. Cardiovasc Res. 2021;117:423–34.
Tannahill GM, Curtis AM, Adamik J, Palsson-McDermott EM, McGettrick AF, Goel G, et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature. 2013;496:238–42.
Wong HS, Dighe PA, Mezera V, Monternier PA, Brand MD. Production of superoxide and hydrogen peroxide from specific mitochondrial sites under different bioenergetic conditions. J Biol Chem. 2017;292:16804–9.
Amin JK, Xiao L, Pimental DR, Pagano PJ, Singh K, Sawyer DB, et al. Reactive oxygen species mediate alpha-adrenergic receptor-stimulated hypertrophy in adult rat ventricular myocytes. J Mol Cell Cardiol. 2001;33:131–9.
Xiao L, Pimentel DR, Wang J, Singh K, Colucci WS, Sawyer DB. Role of reactive oxygen species and NAD(P)H oxidase in alpha(1)-adrenoceptor signaling in adult rat cardiac myocytes. Am J Physiol Cell Physiol. 2002;282:C926–34.
Mittal M, Siddiqui MR, Tran K, Reddy SP, Malik AB. Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal. 2014;20:1126–67.
Zhou B, Tian R. Mitochondrial dysfunction in pathophysiology of heart failure. J Clin Invest. 2018;128:3716–26.
Strassheim D, Dempsey EC, Gerasimovskaya E, Stenmark K, Karoor V. Role of inflammatory cell subtypes in heart failure. J Immunol Res. 2019;2019:2164017.
Redfors B, Vedad R, Angerås O, Råmunddal T, Petursson P, Haraldsson I, et al. Mortality in takotsubo syndrome is similar to mortality in myocardial infarction—a report from the SWEDEHEART registry. Int J Cardiol. 2015;185:282–9.
Isogai T, Matsui H, Tanaka H, Fushimi K, Yasunaga H. Early β-blocker use and in-hospital mortality in patients with Takotsubo cardiomyopathy. Heart. 2016;102:1029–35.
Perez-Riverol Y, Bai J, Bandla C, García-Seisdedos D, Hewapathirana S, Kamatchinathan S, et al. The PRIDE database resources in 2022: a hub for mass spectrometry-based proteomics evidence. Nucleic Acids Res. 2022;50:D543–d52.
This work was supported by the Beijing Municipal Natural Science Foundation [grant number 7191013 to EDD], the National Key R&D Program of China [2021YFF0501401 to HX; 2021YFF1200500 to ZYL], the National Natural Science Foundation of China [grant numbers 82030072, 81822003 to HX; 81830009 to YYZ; 82100280 to JMW], the Haihe Laboratory of Cell Ecosystem Innovation Fund [grant number HH22KYZX0047 to EDD], and the Key Clinical Projects of Peking University Third Hospital [grant number BYSYZD2019022 to HX]. This work was partly supported by grants from Peking-Tsinghua Center for Life Sciences.
The authors declare no competing interests.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Zhang, D., Zhao, Mm., Wu, Jm. et al. Dual-omics reveals temporal differences in acute sympathetic stress-induced cardiac inflammation following α1 and β-adrenergic receptors activation. Acta Pharmacol Sin (2023). https://doi.org/10.1038/s41401-022-01048-5
- adrenergic receptors
- acute sympathetic stress
- cardiac inflammation