α1-AR overactivation induces cardiac inflammation through NLRP3 inflammasome activation

Article metrics

Abstract

Acute sympathetic stress causes excessive secretion of catecholamines and induces cardiac injuries, which are mainly mediated by β-adrenergic receptors (β-ARs). However, α1-adrenergic receptors (α1-ARs) are also expressed in the heart and are activated upon acute sympathetic stress. In the present study, we investigated whether α1-AR activation induced cardiac inflammation and the underlying mechanisms. Male C57BL/6 mice were injected with a single dose of α1-AR agonist phenylephrine (PE, 5 or 10 mg/kg, s.c.) with or without pretreatment with α-AR antagonist prazosin (5 mg/kg, s.c.). PE injection caused cardiac dysfunction and cardiac inflammation, evidenced by the increased expression of inflammatory cytokine IL-6 and chemokines MCP-1 and MCP-5, as well as macrophage infiltration in myocardium. These effects were blocked by prazosin pretreatment. Furthermore, PE injection significantly increased the expression of NOD-like receptor protein 3 (NLRP3) and the cleavage of caspase-1 (p20) and interleukin-18 in the heart; similar results were observed in both Langendorff-perfused hearts and cultured cardiomyocytes following the treatment with PE (10 μM). Moreover, PE-induced NLRP3 inflammasome activation and cardiac inflammation was blocked in Nlrp3-/- mice compared with wild-type mice. In conclusion, α1-AR overactivation induces cardiac inflammation by activating NLRP3 inflammasomes.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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

References

  1. 1.

    Wittstein IS, Thiemann DR, Lima JA, Baughman KL, Schulman SP, Gerstenblith G, et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med. 2005;352:539–48.

  2. 2.

    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.

  3. 3.

    Brodde OE. Beta 1- and beta 2-adrenoceptors in the human heart: properties, function, and alterations in chronic heart failure. Pharmacol Rev. 1991;43:203–42.

  4. 4.

    Huang CJ, Webb HE, Zourdos MC, Acevedo EO. Cardiovascular reactivity, stress, and physical activity. Front Physiol. 2013;4:314.

  5. 5.

    Manolis AJ, Poulimenos LE, Kallistratos MS, Gavras I, Gavras H. Sympathetic overactivity in hypertension and cardiovascular disease. Curr Vasc Pharm. 2014;12:4–15.

  6. 6.

    Xiao H, Li H, Wang JJ, Zhang JS, Shen J, An XB, et al. IL-18 cleavage triggers cardiac inflammation and fibrosis upon beta-adrenergic insult. Eur Heart J. 2018;39:60–9.

  7. 7.

    Pasqua T, Pagliaro P, Rocca C, Angelone T, Penna C. Role of NLRP-3 Inflammasome in hypertension: a potential therapeutic target. Curr Pharm Biotechnol. 2018;19:708–14.

  8. 8.

    Wang Z, Hu W, Lu C, Ma Z, Jiang S, Gu C, et al. Targeting NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3) inflammasome in cardiovascular disorders. Arterioscler Thromb Vasc Biol. 2018;38:2765–79.

  9. 9.

    Toldo S, Mezzaroma E, Mauro AG, Salloum F, Van Tassell BW, Abbate A. The inflammasome in myocardial injury and cardiac remodeling. Antioxid Redox Signal. 2015;22:1146–61.

  10. 10.

    Westman PC, Lipinski MJ, Luger D, Waksman R, Bonow RO, Wu E, et al. Inflammation as a driver of adverse left ventricular remodeling after acute myocardial infarction. J Am Coll Cardiol. 2016;67:2050–60.

  11. 11.

    Wang Y, Thatcher SE, Cassis LA. Blood pressure monitoring using radio telemetry method in mice. Methods Mol Biol. 2017;1614:75–85.

  12. 12.

    Liao R, Podesser BK, Lim CC. The continuing evolution of the Langendorff and ejecting murine heart: new advances in cardiac phenotyping. Am J Physiol Heart Circ Physiol. 2012;303:H156–67.

  13. 13.

    Iwatsubo K, Minamisawa S, Tsunematsu T, Nakagome M, Toya Y, Tomlinson JE, et al. Direct inhibition of type 5 adenylyl cyclase prevents myocardial apoptosis without functional deterioration. J Biol Chem. 2004;279:40938–45.

  14. 14.

    Chen D, Carpenter A, Abrahams J, Chambers RC, Lechler RI, McVey JH, et al. Protease-activated receptor 1 activation is necessary for monocyte chemoattractant protein 1-dependent leukocyte recruitment in vivo. J Exp Med. 2008;205:1739–46.

  15. 15.

    Deshmane SL, Kremlev S, Amini S, Sawaya BE. Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interferon Cytokine Res. 2009;29:313–26.

  16. 16.

    Melendez GC, McLarty JL, Levick SP, Du Y, Janicki JS, Brower GL. Interleukin 6 mediates myocardial fibrosis, concentric hypertrophy, and diastolic dysfunction in rats. Hypertension. 2010;56:225–31.

  17. 17.

    Perez DM, Papay RS, Shi T. alpha1-Adrenergic receptor stimulates interleukin-6 expression and secretion through both mRNA stability and transcriptional regulation: involvement of p38 mitogen-activated protein kinase and nuclear factor-kappaB. Mol Pharmacol. 2009;76:144–52.

  18. 18.

    Koren L, Barash U, Zohar Y, Karin N, Aronheim A. The cardiac maladaptive ATF3-dependent cross-talk between cardiomyocytes and macrophages is mediated by the IFNgamma-CXCL10-CXCR3 axis. Int J Cardiol. 2017;228:394–400.

  19. 19.

    Li R, Lu K, Wang Y, Chen M, Zhang F, Shen H, et al. Triptolide attenuates pressure overload-induced myocardial remodeling in mice via the inhibition of NLRP3 inflammasome expression. Biochem Biophys Res Commun. 2017;485:69–75.

  20. 20.

    Abais JM, Xia M, Zhang Y, Boini KM, Li PL. Redox regulation of NLRP3 inflammasomes: ROS as trigger or effector? Antioxid Redox Signal. 2015;22:1111–29.

  21. 21.

    Moon JS, Nakahira K, Chung KP, DeNicola GM, Koo MJ, Pabon MA, et al. NOX4-dependent fatty acid oxidation promotes NLRP3 inflammasome activation in macrophages. Nat Med. 2016;22:1002–12.

  22. 22.

    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.

  23. 23.

    Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, et al. [2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Task force for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). G Ital Cardiol (Rome). 2016;17:831–72.

Download references

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (81260028 to Li Wang, No. 81530009 to You-yi Zhang and No. 81670205 to Han Xiao), the Fund for Fostering Young Scholars of Peking University Health Science Center (No. BMU2017PY016 to Han Xiao) and the Open Foundation from Beijing Key Laboratory of Hypertension Research (No. 2017GXY-KFKT-05 to Han Xiao).

Author information

YYZ, HX, and LW conceived the project and designed the study. JZX, JMW, GMH, HJG, SXW, WWC, MZL, WLX, and YS performed the experiments. JZX, JMW, and YNF analyzed the data. JZX and JMW wrote the manuscript.

Correspondence to You-yi Zhang or Li Wang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Keywords

  • α1-adrenergic receptor
  • cardiac inflammation
  • NOD-like receptor protein 3
  • inflammasome
  • caspase-1
  • interleukin-18
  • phenylephrine
  • prazosin