Role of TXNIP/NLRP3 in sepsis-induced myocardial dysfunction

Yang,Chun; Xia,Wan; Liu,Xiaolin; Lin,Jian; Wu,Aiping

doi:10.3892/ijmm.2019.4232

Role of TXNIP/NLRP3 in sepsis-induced myocardial dysfunction

Authors:
- Chun Yang
- Wan Xia
- Xiaolin Liu
- Jian Lin
- Aiping Wu
View Affiliations

Affiliations: Department of Emergency Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang 310012, P.R. China, Department of Rehabilitation Medicine, Zhejiang Hospital, Hangzhou, Zhejiang 310013, P.R. China
Published online on: June 6, 2019 https://doi.org/10.3892/ijmm.2019.4232
Pages: 417-426
Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Myocardial injury is one of the main symptoms of sepsis. However, the mechanisms underlying sepsis‑induced myocardial dysfunction remain unclear. In the present study, the concentration of cardiac troponin T (CTnT) in serum was measured using an enzyme‑linked immunosorbent assay kit. The levels of interleukin (IL)‑1β and IL‑18 were assessed by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) analysis and the level of malondialdehyde (MDA) was determined using a corresponding kit. Myocardial pathology was analyzed via hematoxylin and eosin staining. RT‑qPCR analysis and western blotting and/or immunohistochemistry were used to quantify the expression levels of thioredoxin‑interacting protein (TNXIP), NOD‑like receptor pyrin domain containing 3 (NLRP3), cleaved caspase‑1, caspase‑1, catalase and manganese‑superoxide dismutase (MnSOD). The viability of cells was determined using a cell counting kit‑8. Apoptosis and reactive oxygen species (ROS) were examined using flow cytometry. Models of sepsis‑induced myocardial injury were successfully established; evidence included increases in the levels of CTnT, IL‑1β, IL‑18 and MDA and myocardial tissue damage in vivo, and decreased cell viability and improvements in IL‑1β and IL‑18 in vitro. The levels of TXNIP, NLRP3 and cleaved caspase‑1 were upregulated in the sepsis models. Small interfering RNA targeting TNXNIP (siTXNIP) increased cell viability, reduced the apoptotic rate and attenuated the release of IL‑1β and IL‑18. The levels of TXNIP, NLRP3 and cleaved caspase‑1 and production of ROS were suppressed by siTXNIP, accompanied by increases in catalase and MnSOD. TXNIP/NLRP3 serves an important role in the development of sepsis‑induced myocardial damage.

View Figures

View References

1	Xu YB ZH, Chen SZ, Chen GR and Guo S: Optimization and identification of anti-sepsis potential targets of palmatine. Chin J Mod Appl Pharm. 35:1602–1605. 2018.
2	Stanzani G, Duchen MR and Singer M: The role of mitochondria in sepsis-induced cardiomyopathy. Biochim Biophys Acta Mol Basis Dis. 1865:759–773. 2019. View Article : Google Scholar
3	Rabuel C and Mebazaa A: Septic shock: A heart story since the 1960s. Intensive Care Med. 32:799–807. 2006. View Article : Google Scholar : PubMed/NCBI
4	Rudiger A and Singer M: Mechanisms of sepsis-induced cardiac dysfunction. Crit Care Med. 35:1599–1608. 2007. View Article : Google Scholar : PubMed/NCBI
5	Meng F, Lai H, Luo Z, Liu Y, Huang X, Chen J, Liu B, Guo Y, Cai Y and Huang Q: Effect of xuefu zhuyu decoction pretreatment on myocardium in sepsis rats. Evid Based Complement Alternat Med. 2018:29393072018. View Article : Google Scholar : PubMed/NCBI
6	Anthonymuthu TS, Kim-Campbell N and Bayir H: Oxidative lipidomics: Applications in critical care. Curr Opin Crit Care. 23:251–256. 2017. View Article : Google Scholar : PubMed/NCBI
7	Al-Salam S and Hashmi S: Myocardial ischemia reperfusion injury: Apoptotic, inflammatory and oxidative stress role of galectin-3. Cell Physiol Biochem. 50:1123–1139. 2018. View Article : Google Scholar : PubMed/NCBI
8	Su Q, Li L, Sun Y, Yang H, Ye Z and Zhao J: Effects of the TLR4/Myd88/NF-κB signaling pathway on NLRP3 inflammasome in coronary microembolization-induced myocardial injury. Cell Physiol Biochem. 47:1497–1508. 2018. View Article : Google Scholar
9	Kayagaki N, Stowe IB, Lee BL, O'Rourke K, Anderson K, Warming S, Cuellar T, Haley B, Roose-Girma M, Phung QT, et al: Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature. 526:666–671. 2015. View Article : Google Scholar : PubMed/NCBI
10	Chen W, Zhao M, Zhao S, Lu Q, Ni L, Zou C, Lu L, Xu X, Guan H, Zheng Z and Qiu Q: Activation of the TXNIP/NLRP3 inflammasome pathway contributes to inflammation in diabetic retinopathy: A novel inhibitory effect of minocycline. Inflamm Res. 66:157–166. 2017. View Article : Google Scholar
11	Zheng R, Tao L, Jian H, Chang Y, Cheng Y, Feng Y and Zhang H: NLRP3 inflammasome activation and lung fibrosis caused by airborne fine particulate matter. Ecotoxicol Environ Saf. 163:612–619. 2018. View Article : Google Scholar : PubMed/NCBI
12	Takimoto E and Kass DA: Role of oxidative stress in cardiac hypertrophy and remodeling. Hypertension. 49:241–248. 2007. View Article : Google Scholar
13	Haileselassie B, Su E, Pozios I, Niño DF, Liu H, Lu DY, Ventoulis I, Fulton WB, Sodhi CP, Hackam D, et al: Myocardial oxidative stress correlates with left ventricular dysfunction on strain echocardiography in a rodent model of sepsis. Intensive Care Med Exp. 5:212017. View Article : Google Scholar : PubMed/NCBI
14	Assem M, Teyssier JR, Benderitter M, Terrand J, Laubriet A, Javouhey A, David M and Rochette L: Pattern of superoxide dismutase enzymatic activity and RNA changes in rat heart ventricles after myocardial infarction. Am J Pathol. 151:549–555. 1997.PubMed/NCBI
15	Lone MU, Baghel KS, Kanchan RK, Shrivastava R, Malik SA, Tewari BN, Tripathi C, Negi MP, Garg VK, Sharma M, et al: Physical interaction of estrogen receptor with MnSOD: Implication in mitochondrial O2^.− upregulation and mTORC2 potentiation in estrogen-responsive breast cancer cells. Oncogene. 36:1829–1839. 2017. View Article : Google Scholar
16	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
17	Klingenberg C, Kornelisse RF, Buonocore G, Maier RF and Stocker M: Culture-negative early-onset neonatal sepsis-at the crossroad between efficient sepsis care and antimicrobial stewardship. Front Pediatr. 6:2852018. View Article : Google Scholar
18	Liu H, Sun Y, Zhang Y, Yang G, Guo L, Zhao Y and Pei Z: Role of thymoquinone in cardiac damage caused by sepsis from BALB/c mice. Inflammation. 42:516–525. 2019. View Article : Google Scholar
19	Stoll LL, Denning GM and Weintraub NL: Potential role of endotoxin as a proinflammatory mediator of atherosclerosis. Arterioscler Thromb Vasc Biol. 24:2227–2236. 2004. View Article : Google Scholar : PubMed/NCBI
20	Kakihana Y, Ito T, Nakahara M, Yamaguchi K and Yasuda T: Sepsis-induced myocardial dysfunction: Pathophysiology and management. J Intensive Care. 4:222016. View Article : Google Scholar : PubMed/NCBI
21	Iqbal M, Cohen RI, Marzouk K and Liu SF: Time course of nitric oxide, peroxynitrite, and antioxidants in the endotoxemic heart. Crit Care Med. 30:1291–1296. 2002. View Article : Google Scholar : PubMed/NCBI
22	Afulukwe IF, Cohen RI, Zeballos GA, Iqbal M and Scharf SM: Selective NOS inhibition restores myocardial contractility in endotoxemic rats; however, myocardial NO content does not correlate with myocardial dysfunction. Am J Respir Crit Care Med. 162:21–26. 2000. View Article : Google Scholar : PubMed/NCBI
23	Cohen RI, Wilson D and Liu SF: Nitric oxide modifies the sarcoplasmic reticular calcium release channel in endotoxemia by both guanosine-3′,5′ (cyclic) phosphate-dependent and independent pathways. Crit Care Med. 34:173–181. 2006. View Article : Google Scholar
24	Chagnon F, Bentourkia M, Lecomte R, Lessard M and Lesur O: Endotoxin-induced heart dysfunction in rats: Assessment of myocardial perfusion and permeability and the role of fluid resuscitation. Crit Care Med. 34:127–133. 2006. View Article : Google Scholar
25	Maxwell MH, Robertson GW and Moseley D: Potential role of serum troponin T in cardiomyocyte injury in the broiler ascites syndrome. Br Poult Sci. 35:663–667. 1994. View Article : Google Scholar : PubMed/NCBI
26	Choon-ngarm T and Partpisanu P: Serum cardiac troponin-T as a prognostic marker in septic shock. J Med Assoc Thai. 91:1818–1821. 2008.
27	Yang L, Zhang H and Chen P: Sulfur dioxide attenuates sepsis-induced cardiac dysfunction via inhibition of NLRP3 inflammasome activation in rats. Nitric Oxide. 81:11–20. 2018. View Article : Google Scholar : PubMed/NCBI
28	Wu D, Shi L, Li P, Ni X, Zhang J, Zhu Q, Qi Y and Wang B: Intermedin1-53 protects cardiac fibroblasts by inhibiting NLRP3 inflammasome activation during sepsis. Inflammation. 41:505–514. 2018. View Article : Google Scholar
29	Zhang B, Liu Y, Sui YB, Cai HQ, Liu WX, Zhu M and Yin XH: Cortistatin inhibits NLRP3 inflammasome activation of cardiac fibroblasts during sepsis. J Card Fail. 21:426–433. 2015. View Article : Google Scholar : PubMed/NCBI
30	Lopes de Oliveira GA, Alarcón de la Lastra C, Rosillo MÁ, Castejon Martinez ML, Sánchez-Hidalgo M, Rolim Medeiros JV and Villegas I: Preventive effect of bergenin against the development of TNBS-induced acute colitis in rats is associated with inflammatory mediators inhibition and NLRP3/ASC inflammasome signaling pathways. Chem Biol Interact. 297:25–33. 2019. View Article : Google Scholar
31	Shen HH, Yang YX, Meng X, Luo XY, Li XM, Shuai ZW, Ye DQ and Pan HF: NLRP3: A promising therapeutic target for autoimmune diseases. Autoimmun Rev. 17:694–702. 2018. View Article : Google Scholar : PubMed/NCBI
32	Clavier T, Besnier E, Lefevre-Scelles A, Lanfray D, Masmoudi O, Pelletier G, Castel H, Tonon MC and Compère V: Increased hypothalamic levels of endozepines, endogenous ligands of benzodiazepine receptors, in a rat model of sepsis. Shock. 45:653–659. 2016. View Article : Google Scholar : PubMed/NCBI
33	Hara Y, Shimomura Y, Nakamura T, Kuriyama N, Yamashita C, Kato Y, Miyasho T, Sakai T, Yamada S, Moriyama K and Nishida O: Novel blood purification system for regulating excessive immune reactions in severe sepsis and septic shock: An ex vivo pilot study. Ther Apher Dial. 19:308–315. 2015. View Article : Google Scholar : PubMed/NCBI
34	Sandanger Ø, Ranheim T, Vinge LE, Bliksøen M, Alfsnes K, Finsen AV, Dahl CP, Askevold ET, Florholmen G, Christensen G, et al: The NLRP3 inflammasome is up-regulated in cardiac fibroblasts and mediates myocardial ischaemia-reperfusion injury. Cardiovasc Res. 99:164–174. 2013. View Article : Google Scholar : PubMed/NCBI
35	Jin C and Flavell RA: Molecular mechanism of NLRP3 inflammasome activation. J Clin Immunol. 30:628–631. 2010. View Article : Google Scholar : PubMed/NCBI
36	Nishiyama A, Matsui M, Iwata S, Hirota K, Masutani H, Nakamura H, Takagi Y, Sono H, Gon Y and Yodoi J: Identification of thioredoxin-binding protein-2/vitamin D(3) up-regulated protein 1 as a negative regulator of thioredoxin function and expression. J Biol Chem. 274:21645–21650. 1999. View Article : Google Scholar : PubMed/NCBI
37	Liu Y, Lian K, Zhang L, Wang R, Yi F, Gao C, Xin C, Zhu D, Li Y, Yan W, et al: TXNIP mediates NLRP3 inflammasome activation in cardiac microvascular endothelial cells as a novel mechanism in myocardial ischemia/reperfusion injury. Basic Res Cardiol. 109:4152014. View Article : Google Scholar : PubMed/NCBI