Skip to main content

Advertisement

SpringerLink
Log in

The mechanism of 25-hydroxycholesterol-mediated suppression of atrial β1-adrenergic responses

  • Signaling and Cell Physiology
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

25-Hydroxycholesterol (25HC) is a biologically active oxysterol, whose production greatly increases during inflammation by macrophages and dendritic cells. The inflammatory reactions are frequently accompanied by changes in heart regulation, such as blunting of the cardiac β-adrenergic receptor (AR) signaling. Here, the mechanism of 25HC-dependent modulation of responses to β-AR activation was studied in the atria of mice. 25HC at the submicromolar levels decreased the β-AR-mediated positive inotropic effect and enhancement of the Ca2+ transient amplitude, without changing NO production. Positive inotropic responses to β1-AR (but not β2-AR) activation were markedly attenuated by 25HC. The depressant action of 25HC on the β1-AR-mediated responses was prevented by selective β3-AR antagonists as well as inhibitors of Gi protein, Gβγ, G protein-coupled receptor kinase 2/3, or β-arrestin. Simultaneously, blockers of protein kinase D and C as well as a phosphodiesterase inhibitor did not preclude the negative action of 25HC on the inotropic response to β-AR activation. Thus, 25HC can suppress the β1-AR-dependent effects via engaging β3-AR, Gi protein, Gβγ, G protein-coupled receptor kinase, and β-arrestin. This 25HC-dependent mechanism can contribute to the inflammatory-related alterations in the atrial β-adrenergic signaling.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data availability

All mentioned data are represented in the main manuscript figures and supplementary figure. Other additional data will be made available on reasonable request.

Abbreviations

AR:

Adrenoceptor

25HC:

25-Hydroxycholesterol

GRK:

G protein-coupled receptor kinase

NO:

Nitric oxide

ISO:

Isoproterenol

PKC:

Protein kinase C

PKD:

Protein kinase D

PDE:

Phosphodiesterase

References

  1. Adamo L, Rocha-Resende C, Prabhu SD, Mann DL (2020) Reappraising the role of inflammation in heart failure. Nat Rev Cardiol 17:269–285. https://doi.org/10.1038/s41569-019-0315-x

    Article  PubMed  Google Scholar 

  2. Agarwal SR, Sherpa RT, Moshal KS, Harvey RD (2022) Compartmentalized cAMP signaling in cardiac ventricular myocytes. Cell Signal 89:110172. https://doi.org/10.1016/j.cellsig.2021.110172

    Article  CAS  PubMed  Google Scholar 

  3. Algoet M, Janssens S, Himmelreich U, Gsell W, Pusovnik M, Van den Eynde J, Oosterlinck W (2023) Myocardial ischemia-reperfusion injury and the influence of inflammation. Trends Cardiovasc Med 33:357–366. https://doi.org/10.1016/j.tcm.2022.02.005

    Article  CAS  PubMed  Google Scholar 

  4. Arioglu-Inan E, Kayki-Mutlu G, Michel MC (2019) Cardiac beta(3) -adrenoceptors-a role in human pathophysiology? Br J Pharmacol 176:2482–2495. https://doi.org/10.1111/bph.14635

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Baker JG (2010) The selectivity of beta-adrenoceptor agonists at human beta1-, beta2- and beta3-adrenoceptors. Br J Pharmacol 160:1048–1061. https://doi.org/10.1111/j.1476-5381.2010.00754.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Balligand JL (2016) Cardiac salvage by tweaking with beta-3-adrenergic receptors. Cardiovasc Res 111:128–133. https://doi.org/10.1093/cvr/cvw056

    Article  CAS  PubMed  Google Scholar 

  7. Bardswell SC, Cuello F, Rowland AJ, Sadayappan S, Robbins J, Gautel M, Walker JW, Kentish JC, Avkiran M (2010) Distinct sarcomeric substrates are responsible for protein kinase D-mediated regulation of cardiac myofilament Ca2+ sensitivity and cross-bridge cycling. J Biol Chem 285:5674–5682. https://doi.org/10.1074/jbc.M109.066456

    Article  CAS  PubMed  Google Scholar 

  8. Bauman DR, Bitmansour AD, McDonald JG, Thompson BM, Liang G, Russell DW (2009) 25-Hydroxycholesterol secreted by macrophages in response to toll-like receptor activation suppresses immunoglobulin A production. Proc Natl Acad Sci U S A 106:16764–16769. https://doi.org/10.1073/pnas.0909142106

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  9. Beautrait A, Paradis JS, Zimmerman B, Giubilaro J, Nikolajev L, Armando S, Kobayashi H, Yamani L, Namkung Y, Heydenreich FM, Khoury E, Audet M, Roux PP, Veprintsev DB, Laporte SA, Bouvier M (2017) A new inhibitor of the beta-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling. Nat Commun 8:15054. https://doi.org/10.1038/ncomms15054

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  10. Breit A, Lagace M, Bouvier M (2004) Hetero-oligomerization between beta2- and beta3-adrenergic receptors generates a beta-adrenergic signaling unit with distinct functional properties. J Biol Chem 279:28756–28765. https://doi.org/10.1074/jbc.M313310200

    Article  CAS  PubMed  Google Scholar 

  11. Campbell AP, Smrcka AV (2018) Targeting G protein-coupled receptor signalling by blocking G proteins. Nat Rev Drug Discov 17:789–803. https://doi.org/10.1038/nrd.2018.135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cannavo A, Koch WJ (2017) Targeting beta3-adrenergic receptors in the heart: selective agonism and beta-blockade. J Cardiovasc Pharmacol 69:71–78. https://doi.org/10.1097/FJC.0000000000000444

    Article  CAS  PubMed  Google Scholar 

  13. Cannavo A, Liccardo D, Koch WJ (2013) Targeting cardiac beta-adrenergic signaling via GRK2 inhibition for heart failure therapy. Front Physiol 4:264. https://doi.org/10.3389/fphys.2013.00264

    Article  PubMed  PubMed Central  Google Scholar 

  14. Cernecka H, Sand C, Michel MC (2014) The odd sibling: features of beta3-adrenoceptor pharmacology. Mol Pharmacol 86:479–484. https://doi.org/10.1124/mol.114.092817

    Article  CAS  PubMed  Google Scholar 

  15. Chen H, Cao N, Wang L, Wu Y, Wei H, Li Y, Zhang Y, Zhang S, Liu H (2021) Biased activation of beta(2)-AR/Gi/GRK2 signal pathway attenuated beta(1)-AR sustained activation induced by beta(1)-adrenergic receptor autoantibody. Cell Death Discov 7:340. https://doi.org/10.1038/s41420-021-00735-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Christ T, Molenaar P, Klenowski PM, Ravens U, Kaumann AJ (2011) Human atrial beta(1L)-adrenoceptor but not beta(3)-adrenoceptor activation increases force and Ca(2+) current at physiological temperature. Br J Pharmacol 162:823–839. https://doi.org/10.1111/j.1476-5381.2010.00996.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Cuello F, Bardswell SC, Haworth RS, Yin X, Lutz S, Wieland T, Mayr M, Kentish JC, Avkiran M (2007) Protein kinase D selectively targets cardiac troponin I and regulates myofilament Ca2+ sensitivity in ventricular myocytes. Circ Res 100:864–873. https://doi.org/10.1161/01.RES.0000260809.15393.fa

    Article  CAS  PubMed  Google Scholar 

  18. Cyster JG, Dang EV, Reboldi A, Yi T (2014) 25-Hydroxycholesterols in innate and adaptive immunity. Nat Rev Immunol 14:731–743. https://doi.org/10.1038/nri3755

    Article  CAS  PubMed  Google Scholar 

  19. Dalal S, Connelly B, Singh M, Singh K (2018) NF2 signaling pathway plays a pro-apoptotic role in beta-adrenergic receptor stimulated cardiac myocyte apoptosis. PLoS One 13:e0196626. https://doi.org/10.1371/journal.pone.0196626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Devic E, Xiang Y, Gould D, Kobilka B (2001) Beta-adrenergic receptor subtype-specific signaling in cardiac myocytes from beta(1) and beta(2) adrenoceptor knockout mice. Mol Pharmacol 60:577–583

    CAS  PubMed  Google Scholar 

  21. Diczfalusy U, Olofsson KE, Carlsson AM, Gong M, Golenbock DT, Rooyackers O, Flaring U, Bjorkbacka H (2009) Marked upregulation of cholesterol 25-hydroxylase expression by lipopolysaccharide. J Lipid Res 50:2258–2264. https://doi.org/10.1194/jlr.M900107-JLR200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ferrara N, Komici K, Corbi G, Pagano G, Furgi G, Rengo C, Femminella GD, Leosco D, Bonaduce D (2014) beta-adrenergic receptor responsiveness in aging heart and clinical implications. Front Physiol 4:396. https://doi.org/10.3389/fphys.2013.00396

    Article  PubMed  PubMed Central  Google Scholar 

  23. Ferrero KM, Koch WJ (2022) GRK2 in cardiovascular disease and its potential as a therapeutic target. J Mol Cell Cardiol 172:14–23. https://doi.org/10.1016/j.yjmcc.2022.07.008

    Article  CAS  PubMed  Google Scholar 

  24. Gater DL, Saurel O, Iordanov I, Liu W, Cherezov V, Milon A (2014) Two classes of cholesterol binding sites for the beta2AR revealed by thermostability and NMR. Biophys J 107:2305–2312. https://doi.org/10.1016/j.bpj.2014.10.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gc JB, Chen J, Pokharel SM, Mohanty I, Mariasoosai C, Obi P, Panipinto P, Bandyopadhyay S, Bose S, Natesan S (2023) Molecular basis for the recognition of 24-(S)-hydroxycholesterol by integrin alphavbeta3. Sci Rep 13:9166. https://doi.org/10.1038/s41598-023-36040-4

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  26. Guimond J, Mamarbachi AM, Allen BG, Rindt H, Hebert TE (2005) Role of specific protein kinase C isoforms in modulation of beta1- and beta2-adrenergic receptors. Cell Signal 17:49–58. https://doi.org/10.1016/j.cellsig.2004.05.012

    Article  CAS  PubMed  Google Scholar 

  27. Gulick T, Chung MK, Pieper SJ, Lange LG, Schreiner GF (1989) Interleukin 1 and tumor necrosis factor inhibit cardiac myocyte beta-adrenergic responsiveness. Proc Natl Acad Sci U S A 86:6753–6757. https://doi.org/10.1073/pnas.86.17.6753

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  28. Hagiwara S, Iwasaka H, Maeda H, Noguchi T (2009) Landiolol, an ultrashort-acting beta1-adrenoceptor antagonist, has protective effects in an LPS-induced systemic inflammation model. Shock 31:515–520. https://doi.org/10.1097/SHK.0b013e3181863689

    Article  CAS  PubMed  Google Scholar 

  29. Ippolito M, Benovic JL (2021) Biased agonism at beta-adrenergic receptors. Cell Signal 80:109905. https://doi.org/10.1016/j.cellsig.2020.109905

    Article  CAS  PubMed  Google Scholar 

  30. Ishikawa T, Kume H, Kondo M, Ito Y, Yamaki K, Shimokata K (2003) Inhibitory effects of interferon-gamma on the heterologous desensitization of beta-adrenoceptors by transforming growth factor-beta 1 in tracheal smooth muscle. Clin Exp Allergy 33:808–815. https://doi.org/10.1046/j.1365-2222.2003.01681.x

    Article  CAS  PubMed  Google Scholar 

  31. Jamora C, Yamanouye N, Van Lint J, Laudenslager J, Vandenheede JR, Faulkner DJ, Malhotra V (1999) Gbetagamma-mediated regulation of Golgi organization is through the direct activation of protein kinase D. Cell 98:59–68. https://doi.org/10.1016/S0092-8674(00)80606-6

    Article  CAS  PubMed  Google Scholar 

  32. Karam S, Margaria JP, Bourcier A, Mika D, Varin A, Bedioune I, Lindner M, Bouadjel K, Dessillons M, Gaudin F, Lefebvre F, Mateo P, Lechene P, Gomez S, Domergue V, Robert P, Coquard C, Algalarrondo V, Samuel JL et al (2020) Cardiac overexpression of PDE4B blunts beta-adrenergic response and maladaptive remodeling in heart failure. Circulation 142:161–174. https://doi.org/10.1161/CIRCULATIONAHA.119.042573

    Article  CAS  PubMed  Google Scholar 

  33. Kayki-Mutlu G, Karaomerlioglu I, Arioglu-Inan E, Altan VM (2019) Beta-3 adrenoceptors: a potential therapeutic target for heart disease. Eur J Pharmacol 858:172468. https://doi.org/10.1016/j.ejphar.2019.172468

    Article  CAS  PubMed  Google Scholar 

  34. Khamssi M, Brodde OE (1990) The role of cardiac beta1- and beta2-adrenoceptor stimulation in heart failure. J Cardiovasc Pharmacol 16(Suppl 5):S133–S137

    Article  PubMed  Google Scholar 

  35. Lappano R, Recchia AG, De Francesco EM, Angelone T, Cerra MC, Picard D, Maggiolini M (2011) The cholesterol metabolite 25-hydroxycholesterol activates estrogen receptor alpha-mediated signaling in cancer cells and in cardiomyocytes. PLoS One 6:e16631. https://doi.org/10.1371/journal.pone.0016631

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  36. Liu Y, Wei Z, Ma X, Yang X, Chen Y, Sun L, Ma C, Miao QR, Hajjar DP, Han J, Duan Y (2018) 25-Hydroxycholesterol activates the expression of cholesterol 25-hydroxylase in an LXR-dependent mechanism. J Lipid Res 59:439–451. https://doi.org/10.1194/jlr.M080440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. MacNeil BJ, Jansen AH, Greenberg AH, Nance DM (1996) Activation and selectivity of splenic sympathetic nerve electrical activity response to bacterial endotoxin. Am J Physiol 270:R264–R270. https://doi.org/10.1152/ajpregu.1996.270.1.R264

    Article  CAS  PubMed  Google Scholar 

  38. Mahmood A, Ahmed K, Zhang Y (2022) Beta-adrenergic receptor desensitization/down-regulation in heart failure: a friend or foe? Front Cardiovasc Med 9:925692. https://doi.org/10.3389/fcvm.2022.925692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Massion PB, Pelat M, Belge C, Balligand JL (2005) Regulation of the mammalian heart function by nitric oxide. Comp Biochem Physiol A Mol Integr Physiol 142:144–150. https://doi.org/10.1016/j.cbpb.2005.05.048

    Article  CAS  PubMed  Google Scholar 

  40. Matsuda N, Hattori Y, Akaishi Y, Suzuki Y, Kemmotsu O, Gando S (2000) Impairment of cardiac beta-adrenoceptor cellular signaling by decreased expression of G(s alpha) in septic rabbits. Anesthesiology 93:1465–1473. https://doi.org/10.1097/00000542-200012000-00019

    Article  CAS  PubMed  Google Scholar 

  41. Mira Hernandez J, Ko CY, Mandel AR, Shen EY, Baidar S, Christensen AR, Hellgren K, Morotti S, Martin JL, Hegyi B, Bossuyt J, Bers DM (2023) Cardiac protein kinase D1 ablation alters the myocytes beta-adrenergic response. J Mol Cell Cardiol 180:33–43. https://doi.org/10.1016/j.yjmcc.2023.05.001

    Article  CAS  PubMed  Google Scholar 

  42. Mongillo M, Tocchetti CG, Terrin A, Lissandron V, Cheung YF, Dostmann WR, Pozzan T, Kass DA, Paolocci N, Houslay MD, Zaccolo M (2006) Compartmentalized phosphodiesterase-2 activity blunts beta-adrenergic cardiac inotropy via an NO/cGMP-dependent pathway. Circ Res 98:226–234. https://doi.org/10.1161/01.RES.0000200178.34179.93

    Article  CAS  PubMed  Google Scholar 

  43. Mukai H, Munekata E, Higashijima T (1992) G protein antagonists. A novel hydrophobic peptide competes with receptor for G protein binding. J Biol Chem 267:16237–16243

    Article  CAS  PubMed  Google Scholar 

  44. Neely OC, Domingos AI, Paterson DJ (2021) Macrophages can drive sympathetic excitability in the early stages of hypertension. Front Cardiovasc Med 8:807904. https://doi.org/10.3389/fcvm.2021.807904

    Article  CAS  PubMed  Google Scholar 

  45. Neumann J, Boknik P, Matherne GP, Lankford A, Schmitz W (2003) Pertussis toxin sensitive and insensitive effects of adenosine and carbachol in murine atria overexpressing A(1)-adenosine receptors. Br J Pharmacol 138:209–217. https://doi.org/10.1038/sj.bjp.0705012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Nso N, Bookani KR, Metzl M, Radparvar F (2021) Role of inflammation in atrial fibrillation: a comprehensive review of current knowledge. J Arrhythm 37:1–10. https://doi.org/10.1002/joa3.12473

    Article  PubMed  Google Scholar 

  47. Odnoshivkina YG, Petrov AM (2021) The role of neuro-cardiac junctions in sympathetic regulation of the heart. J Evol Biochem Physiol 57:527–541. https://doi.org/10.1134/s0022093021030078

    Article  Google Scholar 

  48. Odnoshivkina UG, Petrov AM (2023) Immune oxysterol downregulates the atrial inotropic response to β-adrenergic receptor stimulation: the role of liver X receptors and lipid raft stability. J Evol Biochem Physiol 58:S1–S12. https://doi.org/10.1134/s0022093022070018

    Article  CAS  Google Scholar 

  49. Odnoshivkina UG, Sytchev VI, Nurullin LF, Giniatullin AR, Zefirov AL, Petrov AM (2015) β2-adrenoceptor agonist-evoked reactive oxygen species generation in mouse atria: implication in delayed inotropic effect. Eur J Pharmacol 765:140–153. https://doi.org/10.1016/j.ejphar.2015.08.020

    Article  CAS  PubMed  Google Scholar 

  50. Odnoshivkina YG, Sytchev VI, Petrov AM (2017) Cholesterol regulates contractility and inotropic response to beta2-adrenoceptor agonist in the mouse atria: involvement of Gi-protein-Akt-NO-pathway. J Mol Cell Cardiol 107:27–40. https://doi.org/10.1016/j.yjmcc.2016.05.001

    Article  CAS  PubMed  Google Scholar 

  51. Odnoshivkina UG, Sytchev VI, Starostin O, Petrov AM (2019) Brain cholesterol metabolite 24-hydroxycholesterol modulates inotropic responses to beta-adrenoceptor stimulation: The role of NO and phosphodiesterase. Life Sci 220:117–126. https://doi.org/10.1016/j.lfs.2019.01.054

    Article  CAS  PubMed  Google Scholar 

  52. Odnoshivkina UG, Kuznetsova EA, Petrov AM (2022) 25-Hydroxycholesterol as a signaling molecule of the nervous system. Biochemistry (Mosc) 87:524–537. https://doi.org/10.1134/S0006297922060049

    Article  CAS  PubMed  Google Scholar 

  53. Okyere AD, Song J, Patwa V, Carter RL, Enjamuri N, Lucchese AM, Ibetti J, de Lucia C, Schumacher SM, Koch WJ, Cheung JY, Benovic JL, Tilley DG (2023) Pepducin ICL1-9-mediated beta2-adrenergic receptor-dependent cardiomyocyte contractility occurs in a G(i) protein/ROCK/PKD-sensitive manner. Cardiovasc Drugs Ther 37:245–256. https://doi.org/10.1007/s10557-021-07299-4

    Article  CAS  PubMed  Google Scholar 

  54. Pardini BJ, Jones SB, Filkins JP (1983) Cardiac and splenic norepinephrine turnovers in endotoxic rats. Am J Physiol 245:H276–H283. https://doi.org/10.1152/ajpheart.1983.245.2.H276

    Article  CAS  PubMed  Google Scholar 

  55. Penela P, Ribas C, Sanchez-Madrid F, Mayor F Jr (2019) G protein-coupled receptor kinase 2 (GRK2) as a multifunctional signaling hub. Cell Mol Life Sci 76:4423–4446. https://doi.org/10.1007/s00018-019-03274-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Pfleger J, Gresham K, Koch WJ (2019) G protein-coupled receptor kinases as therapeutic targets in the heart. Nat Rev Cardiol 16:612–622. https://doi.org/10.1038/s41569-019-0220-3

    Article  PubMed  Google Scholar 

  57. Poli G, Leoni V, Biasi F, Canzoneri F, Risso D, Menta R (2022) Oxysterols: from redox bench to industry. Redox Biol 49:102220. https://doi.org/10.1016/j.redox.2021.102220

    Article  CAS  PubMed  Google Scholar 

  58. Pott C, Brixius K, Bundkirchen A, Bolck B, Bloch W, Steinritz D, Mehlhorn U, Schwinger RH (2003) The preferential beta3-adrenoceptor agonist BRL 37344 increases force via beta1-/beta2-adrenoceptors and induces endothelial nitric oxide synthase via beta3-adrenoceptors in human atrial myocardium. Br J Pharmacol 138:521–529. https://doi.org/10.1038/sj.bjp.0705065

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Ramesh P, Yeo JL, Brady EM, McCann GP (2022) Role of inflammation in diabetic cardiomyopathy. Ther Adv Endocrinol Metab 13:20420188221083530. https://doi.org/10.1177/20420188221083530

    Article  PubMed  PubMed Central  Google Scholar 

  60. Richter W, Day P, Agrawal R, Bruss MD, Granier S, Wang YL, Rasmussen SG, Horner K, Wang P, Lei T, Patterson AJ, Kobilka B, Conti M (2008) Signaling from beta1- and beta2-adrenergic receptors is defined by differential interactions with PDE4. EMBO J 27:384–393. https://doi.org/10.1038/sj.emboj.7601968

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Rozengurt E (2011) Protein kinase D signaling: multiple biological functions in health and disease. Physiology (Bethesda) 26:23–33. https://doi.org/10.1152/physiol.00037.2010

    Article  CAS  PubMed  Google Scholar 

  62. Rudokas MW, Post JP, Sataray-Rodriguez A, Sherpa RT, Moshal KS, Agarwal SR, Harvey RD (2021) Compartmentation of beta(2) -adrenoceptor stimulated cAMP responses by phosphodiesterase types 2 and 3 in cardiac ventricular myocytes. Br J Pharmacol 178:1574–1587. https://doi.org/10.1111/bph.15382

    Article  CAS  PubMed  Google Scholar 

  63. Sanchez-Alonso JL, Fedele L, Copier JS, Lucarelli C, Mansfield C, Judina A, Houser SR, Brand T, Gorelik J (2023) Functional LTCC-beta(2)AR complex needs caveolin-3 and is disrupted in heart failure. Circ Res 133:120–137. https://doi.org/10.1161/CIRCRESAHA.123.322508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Shi Q, Li M, Mika D, Fu Q, Kim S, Phan J, Shen A, Vandecasteele G, Xiang YK (2017) Heterologous desensitization of cardiac beta-adrenergic signal via hormone-induced betaAR/arrestin/PDE4 complexes. Cardiovasc Res 113:656–670. https://doi.org/10.1093/cvr/cvx036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Simsek Papur O, Sun A, Glatz JFC, Luiken J, Nabben M (2018) Acute and chronic effects of protein kinase-D signaling on cardiac energy metabolism. Front Cardiovasc Med 5:65. https://doi.org/10.3389/fcvm.2018.00065

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Sytchev VI, Odnoshivkina YG, Ursan RV, Petrov AM (2017) Oxysterol, 5alpha-cholestan-3-one, modulates a contractile response to beta2-adrenoceptor stimulation in the mouse atria: Involvement of NO signaling. Life Sci 188:131–140. https://doi.org/10.1016/j.lfs.2017.09.006

    Article  CAS  PubMed  Google Scholar 

  67. Thangamalai R, Kandasamy K, Sukumarn SV, Reddy N, Singh V, Choudhury S, Parida S, Singh TU, Boobalan R, Mishra SK (2014) Atorvastatin prevents sepsis-induced downregulation of myocardial beta1-adrenoceptors and decreased cAMP response in mice. Shock 41:406–412. https://doi.org/10.1097/SHK.0000000000000138

    Article  CAS  PubMed  Google Scholar 

  68. Ursan R, Odnoshivkina UG, Petrov AM (2019) Membrane cholesterol oxidation downregulates atrial beta-adrenergic responses in ROS-dependent manner. Cell Signal 67:109503. https://doi.org/10.1016/j.cellsig.2019.109503

    Article  CAS  PubMed  Google Scholar 

  69. Vielma AZ, Leon L, Fernandez IC, Gonzalez DR, Boric MP (2016) Nitric oxide synthase 1 modulates basal and beta-adrenergic-stimulated contractility by rapid and reversible redox-dependent S-nitrosylation of the heart. PLoS One 11:e0160813. https://doi.org/10.1371/journal.pone.0160813

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Volovyk ZM, Wolf MJ, Prasad SV, Rockman HA (2006) Agonist-stimulated beta-adrenergic receptor internalization requires dynamic cytoskeletal actin turnover. J Biol Chem 281:9773–9780. https://doi.org/10.1074/jbc.M511435200

    Article  CAS  PubMed  Google Scholar 

  71. Wang Y, Wang Y, Yang D, Yu X, Li H, Lv X, Lu D, Wang H (2015) beta(1)-adrenoceptor stimulation promotes LPS-induced cardiomyocyte apoptosis through activating PKA and enhancing CaMKII and IkappaBalpha phosphorylation. Crit Care 19:76. https://doi.org/10.1186/s13054-015-0820-1

    Article  PubMed  PubMed Central  Google Scholar 

  72. Wang Q, Wang Y, West TM, Liu Y, Reddy GR, Barbagallo F, Xu B, Shi Q, Deng B, Wei W, Xiang YK (2021) Carvedilol induces biased beta1 adrenergic receptor-nitric oxide synthase 3-cyclic guanylyl monophosphate signalling to promote cardiac contractility. Cardiovasc Res 117:2237–2251. https://doi.org/10.1093/cvr/cvaa266

    Article  CAS  PubMed  Google Scholar 

  73. Woo AY, Xiao RP (2012) beta-Adrenergic receptor subtype signaling in heart: from bench to bedside. Acta Pharmacol Sin 33:335–341. https://doi.org/10.1038/aps.2011.201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Xiao H, Li H, Wang JJ, Zhang JS, Shen J, An XB, Zhang CC, Wu JM, Song Y, Wang XY, Yu HY, Deng XN, Li ZJ, Xu M, Lu ZZ, Du J, Gao W, Zhang AH, Feng Y, Zhang YY (2018) IL-18 cleavage triggers cardiac inflammation and fibrosis upon beta-adrenergic insult. Eur Heart J 39:60–69. https://doi.org/10.1093/eurheartj/ehx261

    Article  CAS  PubMed  Google Scholar 

  75. Yang P, Chen Z, Huang W, Zhang J, Zou L, Wang H (2023) Communications between macrophages and cardiomyocytes. Cell Commun Signal 21:206. https://doi.org/10.1186/s12964-023-01202-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Zakyrjanova GF, Tsentsevitsky AN, Kuznetsova EA, Petrov AM (2021) Immune-related oxysterol modulates neuromuscular transmission via non-genomic liver X receptor-dependent mechanism. Free Radic Biol Med 174:121–134. https://doi.org/10.1016/j.freeradbiomed.2021.08.013

    Article  CAS  PubMed  Google Scholar 

  77. Zhai R, Snyder J, Montgomery S, Sato PY (2022) Double life: how GRK2 and beta-arrestin signaling participate in diseases. Cell Signal 94:110333. https://doi.org/10.1016/j.cellsig.2022.110333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Zhang ZS, Cheng HJ, Onishi K, Ohte N, Wannenburg T, Cheng CP (2005) Enhanced inhibition of L-type Ca2+ current by beta3-adrenergic stimulation in failing rat heart. J Pharmacol Exp Ther 315:1203–1211. https://doi.org/10.1124/jpet.105.089672

    Article  CAS  PubMed  Google Scholar 

  79. Zhang X, Zheng M, Kim KM (2020) GRK2-mediated receptor phosphorylation and Mdm2-mediated beta-arrestin2 ubiquitination drive clathrin-mediated endocytosis of G protein-coupled receptors. Biochem Biophys Res Commun 533:383–390. https://doi.org/10.1016/j.bbrc.2020.09.030

    Article  CAS  PubMed  Google Scholar 

  80. Michel LYM, Farah C, Balligand JL (2020) The beta3 adrenergic receptor in healthy and pathological cardiovascular tissues. Cells 9. https://doi.org/10.3390/cells9122584

  81. Manna M, Niemela M, Tynkkynen J, Javanainen M, Kulig W, Muller DJ, Rog T, Vattulainen I (2016) Mechanism of allosteric regulation of beta(2)-adrenergic receptor by cholesterol. Elife 5. https://doi.org/10.7554/eLife.18432

  82. Kawaguchi S, Okada M (2021) Cardiac metabolism in sepsis. Metabolites 11. https://doi.org/10.3390/metabo11120846

  83. de Freitas FA, Levy D, Reichert CO, Cunha-Neto E, Kalil J, Bydlowski SP (2022) Effects of Oxysterols on Immune Cells and Related Diseases. Cells 11. https://doi.org/10.3390/cells11081251

  84. Berthouze-Duquesnes M, Lucas A, Sauliere A, Sin YY, Laurent AC, Gales C, Baillie G, Lezoualc’h F (2013) Specific interactions between Epac1, beta-arrestin2 and PDE4D5 regulate beta-adrenergic receptor subtype differential effects on cardiac hypertrophic signaling. Cell Signal 25:970-980. https://doi.org/10.1016/j.cellsig.2012.12.007

Download references

Acknowledgements

We thank Dr. Nicole El-Darzi (Case Western Reserve University) for helpful comments on the manuscript and Dr. Andrey Zakharov (Kazan Federal University) for excellent technical assistance.

Funding

This work was supported by the Russian Science Foundation (grant no. 22-25-00396, https://rscf.ru/project/22-25-00396/).

Author information

Authors and Affiliations

  1. Kazan State Medical University, 49 Butlerova St, Kazan, RT, Russia, 420012

    Julia G. Odnoshivkina, Ildar R. Khakimov, Nazar A. Trusov, Diliara A. Trusova & Alexey M. Petrov

  2. Laboratory of Biophysics of Synaptic Processes, Kazan Institute of Biochemistry and Biophysics, FRC Kazan Scientific Center of RAS, 2/31 Lobachevsky St, Kazan, RT, Russia, 420111

    Julia G. Odnoshivkina & Alexey M. Petrov

  3. Institute of Cell Biophysics, Federal Research Center “Pushchino Scientific Center of Biological Research”, Pushchino Branch, Russian Academy of Sciences, Pushchino, 142290, Russia

    Alexey S. Averin

  4. Kazan Federal University, 18 Kremlyovskaya Street, Kazan, Russia, 420008

    Alexey M. Petrov

Authors
  1. Julia G. Odnoshivkina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alexey S. Averin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ildar R. Khakimov
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nazar A. Trusov
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Diliara A. Trusova
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alexey M. Petrov
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JGO supervised the study, prepared Figures 1–6, and performed experiments (calcium imaging, contraction recording); IRK, NAT, and DAT performed experiments (DAR-4M AM); ASA performed experiments (contraction recording) and prepared supplementary figure 1; AMP wrote the main manuscript text. AMP and JGO designed of the work. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Alexey M. Petrov.

Ethics declarations

Ethics approval

The experimental protocol met the requirements of the EU Directive 2010/63/EU and was approved by the Local Ethical Committee of Kazan Medical University (Protocol #5 / May 27, 2014). The current study was conducted in compliance with the NIH Guide for the Care and Use of Laboratory Animals. Research does not involve human patients.

Consent to participate

Not applicable.

Consent for publication

All authors agree with the content of the manuscript, reviewed the manuscript, approved the final version. All authors consent to publication.

Competing interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. All authors consent to publish the article.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

ESM 1

(DOCX 250 kb)

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.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Odnoshivkina, J.G., Averin, A.S., Khakimov, I.R. et al. The mechanism of 25-hydroxycholesterol-mediated suppression of atrial β1-adrenergic responses. Pflugers Arch - Eur J Physiol 476, 407–421 (2024). https://doi.org/10.1007/s00424-024-02913-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-024-02913-4

Keywords

Search

Navigation