Intermedin1–53 Protects Cardiac Fibroblasts by Inhibiting NLRP3 Inflammasome Activation During Sepsis
- 152 Downloads
Sepsis is a disease that occurs as a result of systemic inflammatory response syndrome (SIRS) in response to an infection, contributing to multiple organ dysfunction and a high mortality rate. Interleukin-lβ (IL-1β) is a cytokine that plays critical roles in inflammation and cardiac dysfunction during severe sepsis. Intermedin1–53 (IMD1–53) has been recently discovered to possess potential endogenous anti-inflammatory and strong cardiovascular protective effects. To investigate whether IMD1–53 can inhibit the NLRP3/caspase-1/IL-1β pathway to alleviate cardiac injury and rescue heart function, sepsis was induced in vivo by caecal ligation and puncture (CLP) surgery, and lipopolysaccharides were used as septic stressors for cardiac fibroblasts (CFs) in vitro. The expressions of IMD1–53 receptors in sepsis rat heart were increased. After IMD1–53 treatment, inflammation caused by sepsis in vivo was greatly reduced, as shown by the downregulation of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), nucleotide-binding domain and leucine-rich repeat containing family, pyrin containing 3 (NLRP3), pro-IL-1β, caspase 1, and nuclear translocation of nuclear factor-κB (NF-kB) protein levels. In addition, cardiac function was significantly improved and mean arterial blood pressure (MABP) increased by 34.8% (P < 0.05) which almost back to normal. Surprisingly, IMD1–53 inhibited cell apoptosis, as caspase 3 activity and Bax expression was significantly reduced in the heart upon IMD1–53 treatment. IMD1–53 abolished the upregulation of ASC, NLRP3, and caspase 1 protein levels in CFs induced by lipopolysaccharide (LPS). IMD1–53 increased cell survival rates and inhibited IL-1β production in the cell culture medium. IMD1–53 can protect against inflammation and heart injury during sepsis via attenuating the NLRP3/caspase-1/IL-1β pathway.
KEY WORDSintermedin1–53 sepsis heart failure NLRP3 inflammasome IL-1β cardiac fibroblasts
This study is supported by the Research Foundation of the Aerospace Central Hospital (NO. YN201316 to Bin Wang) and the National Natural Sciences Foundation of China (NO. 81670434 to Yongfen Qi).
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflicts of interest.
- 2.Bone, R.C., R.A. Balk, F.B. Cerra, R.P. Dellinger, A.M. Fein, W.A. Knaus, R. Schein, et al. 1992. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Critical Care Medicine 20 (6): 864–874.CrossRefGoogle Scholar
- 3.Chang, J.R., X.H. Duan, B.H. Zhang, X. Teng, Y.B. Zhou, Y. Liu, Y.R. Yu, Y. Zhu, C.S. Tang, and Y.F. Qi. 2013. Intermedin1-53 attenuates vascular smooth muscle cell calcification by inhibiting endoplasmic reticulum stress via cyclic adenosine monophosphate/protein kinase A pathway. Experimental Biology and Medicine (Maywood, N.J.) 238 (10): 1136–1146. https://doi.org/10.1177/1535370213502619.CrossRefGoogle Scholar
- 7.Fisher, C.J., Jr., J.F. Dhainaut, S.M. Opal, J.P. Pribble, R.A. Balk, G.J. Slotman, T.J. Iberti, et al. 1994. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group. JAMA 271 (23): 1836–1843.CrossRefPubMedGoogle Scholar
- 8.Fisher, C.J., Jr., G.J. Slotman, S.M. Opal, J.P. Pribble, R.C. Bone, G. Emmanuel, D. Ng, D.C. Bloedow, M.A. Catalano, and Il-Ra Sepsis Syndrome Study Group. 1994. Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: a randomized, open-label, placebo-controlled multicenter trial. Critical Care Medicine 22 (1): 12–21.CrossRefPubMedGoogle Scholar
- 9.Furian, T., C. Aguiar, K. Prado, R.V. Ribeiro, L. Becker, N. Martinelli, N. Clausell, L.E. Rohde, and A. Biolo. 2012. Ventricular dysfunction and dilation in severe sepsis and septic shock: relation to endothelial function and mortality. Journal of Critical Care 27 (3): 319 e319–319 e315. https://doi.org/10.1016/j.jcrc.2011.06.017.CrossRefGoogle Scholar
- 10.Hagiwara, M., G. Bledsoe, Z.R. Yang, R.S. Smith Jr., L. Chao, and J. Chao. 2008. Intermedin ameliorates vascular and renal injury by inhibition of oxidative stress. American Journal of Physiology. Renal Physiology 295 (6): F1735–F1743. https://doi.org/10.1152/ajprenal.90427.2008.PubMedCentralCrossRefPubMedGoogle Scholar
- 11.He, L., X. Peng, J. Zhu, X. Chen, H. Liu, C. Tang, Z. Dong, F. Liu, and Y. Peng. 2014. Mangiferin attenuate sepsis-induced acute kidney injury via antioxidant and anti-inflammatory effects. American Journal of Nephrology 40 (5): 441–450. https://doi.org/10.1159/000369220.CrossRefPubMedGoogle Scholar
- 12.Hesse, D.G., K.J. Tracey, Y. Fong, K.R. Manogue, M.A. Palladino Jr., A. Cerami, G.T. Shires, and S.F. Lowry. 1988. Cytokine appearance in human endotoxemia and primate bacteremia. Surgery, Gynecology & Obstetrics 166 (2): 147–153.Google Scholar
- 19.Luo, Y.P., L. Jiang, K. Kang, D.S. Fei, X.L. Meng, C.C. Nan, S.H. Pan, M.R. Zhao, and M.Y. Zhao. 2014. Hemin inhibits NLRP3 inflammasome activation in sepsis-induced acute lung injury, involving heme oxygenase-1. International Immunopharmacology 20 (1): 24–32. https://doi.org/10.1016/j.intimp.2014.02.017.CrossRefPubMedGoogle Scholar
- 20.Makara, M.A., K.V. Hoang, L.P. Ganesan, E.D. Crouser, J.S. Gunn, J. Turner, L.S. Schlesinger, P.J. Mohler, and M.V. Rajaram. 2016. Cardiac electrical and structural changes during bacterial infection: an instructive model to study cardiac dysfunction in sepsis. Journal of the American Heart Association 5 (9). https://doi.org/10.1161/JAHA.116.003820.
- 24.Morelli, A., S. De Castro, J.L. Teboul, M. Singer, M. Rocco, G. Conti, L. De Luca, et al. 2005. Effects of levosimendan on systemic and regional hemodynamics in septic myocardial depression. Intensive Care Medicine 31 (5): 638–644. https://doi.org/10.1007/s00134-005-2619-z.CrossRefPubMedGoogle Scholar
- 27.Potz, B.A., F.W. Sellke, and M.R. Abid. 2016. Endothelial ROS and impaired myocardial oxygen consumption in sepsis-induced cardiac dysfunction. Journal of Intensive Critical Care 2 (1).Google Scholar
- 29.Rudiger, A., and M. Singer. 2007. Mechanisms of sepsis-induced cardiac dysfunction. Critical Care Medicine 35 (6): 1599–1608. https://doi.org/10.1097/01.CCM.0000266683.64081.02.CrossRefPubMedGoogle Scholar
- 32.Teng, X., J. Song, G. Zhang, Y. Cai, F. Yuan, J. Du, C. Tang, and Y. Qi. 2011. Inhibition of endoplasmic reticulum stress by intermedin(1-53) protects against myocardial injury through a PI3 kinase-Akt signaling pathway. Journal of Molecular Medicine (Berlin, Germany) 89 (12): 1195–1205. https://doi.org/10.1007/s00109-011-0808-5.CrossRefGoogle Scholar
- 37.Wu, R., S. Tang, M. Wang, X. Xu, C. Yao, and S. Wang. 2016. MicroRNA-497 induces apoptosis and suppresses proliferation via the Bcl-2/Bax-caspase9-caspase3 pathway and cyclin D2 protein in HUVECs. PLoS One 11 (12): e0167052. https://doi.org/10.1371/journal.pone.0167052.PubMedCentralCrossRefPubMedGoogle Scholar
- 38.Wu, Y., J. Ren, B. Zhou, C. Ding, J. Chen, G. Wang, G. Gu, et al. 2015. Gene silencing of non-obese diabetic receptor family (NLRP3) protects against the sepsis-induced hyper-bile acidaemia in a rat model. Clinical and Experimental Immunology 179 (2): 277–293. https://doi.org/10.1111/cei.12457.PubMedCentralCrossRefPubMedGoogle Scholar
- 41.Zhang, B., Y. Liu, J.S. Zhang, X.H. Zhang, W.J. Chen, X.H. Yin, and Y.F. Qi. 2015. Cortistatin protects myocardium from endoplasmic reticulum stress induced apoptosis during sepsis. Molecular and Cellular Endocrinology 406: 40–48. https://doi.org/10.1016/j.mce.2015.02.016.CrossRefPubMedGoogle Scholar
- 42.Zhang, J.S., Y.L. Hou, W.W. Lu, X.Q. Ni, F. Lin, Y.R. Yu, C.S. Tang, and Y.F. Qi. 2016. Intermedin1-53 protects against myocardial fibrosis by inhibiting endoplasmic reticulum stress and inflammation induced by homocysteine in apolipoprotein E-deficient mice. Journal of Atherosclerosis and Thrombosis 23 (11): 1294–1306. https://doi.org/10.5551/jat.34082.PubMedCentralCrossRefPubMedGoogle Scholar
- 43.Zhang, W., X. Xu, R. Kao, T. Mele, P. Kvietys, C.M. Martin, and T. Rui. 2014. Cardiac fibroblasts contribute to myocardial dysfunction in mice with sepsis: the role of NLRP3 inflammasome activation. PLoS One 9 (9): e107639. https://doi.org/10.1371/journal.pone.0107639.PubMedCentralCrossRefPubMedGoogle Scholar