Estrogen receptor α mediates the effects of notoginsenoside R1 on endotoxin-induced inflammatory and apoptotic responses in H9c2 cardiomyocytes

Zhong,Lei; Zhou,Xing‑Lu; Liu,Yan‑Song; Wang,Yi‑Min; Ma,Fei; Guo,Bao‑Liang; Yan,Zhao‑Qi; Zhang,Qing‑Yuan

doi:10.3892/mmr.2015.3394

Estrogen receptor α mediates the effects of notoginsenoside R1 on endotoxin-induced inflammatory and apoptotic responses in H9c2 cardiomyocytes

Authors:
- Lei Zhong
- Xing‑Lu Zhou
- Yan‑Song Liu
- Yi‑Min Wang
- Fei Ma
- Bao‑Liang Guo
- Zhao‑Qi Yan
- Qing‑Yuan Zhang
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Affiliations: Department of General Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China, Department of Internal Medicine, Cancer Hospital Affiliated to Harbin Medical University, Harbin, Heilongjiang 150040, P.R. China
Published online on: February 27, 2015 https://doi.org/10.3892/mmr.2015.3394
Pages: 119-126
Copyright: © Zhong et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Estrogen receptors (ERs) are important for preventing endotoxin‑induced myocardial dysfunction. Therefore, plant‑derived phytoestrogens, which target ERs may also affect endotoxin‑induced toxicity in cardiomyocytes. Our previous study revealed that notoginsenoside‑R1 (NG‑R1), a predominant phytoestrogen from Panax notoginseng, protects against cardiac dysfunction. However, the effects of NG‑R1 on cardiomyocytes and the precise cellular/molecular mechanisms underlying its action remain to be elucidated. In the present study, pretreatment with NG‑R1 suppressed the lipopolysaccharide (LPS)‑induced degradation of inhibitor of nuclear factor‑κB (NF‑κB) α, the activation of NF‑κB and caspase‑3, and the subsequent myocardial inflammatory and apoptotic responses in H9c2 cardiomyocytes. An increase in the mRNA and protein expression of ERα was also observed in the NG‑R1‑treated cardiomyocytes. However, the expression pattern of ERβ remained unaltered. Furthermore, the cardioprotective properties of NG‑R1 against LPS‑induced apoptosis and the inflammatory response in cardiomyocytes were attenuated by ICI 182780, a non‑selective ERα antagonist, and methyl‑piperidino‑pyrazole, a selective ERα antagonist. These findings suggested that NG‑R1 reduced endotoxin‑induced cardiomyocyte apoptosis and the inflammatory response via the activation of ERα. Therefore, NG‑R1 exerted direct anti‑inflammatory and anti‑apoptotic effects on the cardiomyocytes, representing a potent agent for the treatment of myocardial inflammation during septic shock.

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1	Merx MW and Weber C: Sepsis and the heart. Circulation. 116:793–802. 2007. View Article : Google Scholar : PubMed/NCBI
2	Crouser E, Exline M, Knoell D and Wewers MD: Sepsis: links between pathogen sensing and organ damage. Curr Pharm Des. 14:1840–1852. 2008. View Article : Google Scholar : PubMed/NCBI
3	Martin GS, Mannino DM, Eaton S and Moss M: The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 348:1546–1554. 2003. 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	Baumgarten G, Knuefermann P, Schuhmacher G, et al: Toll-like receptor 4, nitric oxide, and myocardial depression in endotoxemia. Shock. 25:43–49. 2006. View Article : Google Scholar
6	Hickson-Bick DL, Jones C and Buja LM: Stimulation of mitochondrial biogenesis and autophagy by lipopolysaccharide in the neonatal rat cardiomyocyte protects against programmed cell death. J Mol Cell Cardiol. 44:411–418. 2008. View Article : Google Scholar
7	Zanotti-Cavazzoni SL and Hollenberg SM: Cardiac dysfunction in severe sepsis and septic shock. Curr Opin Crit Care. 15:392–397. 2009. View Article : Google Scholar : PubMed/NCBI
8	Davani EY, Boyd JH, Dorscheid DR, et al: Cardiac ICAM-1 mediates leukocyte-dependent decreased ventricular contractility in endotoxemic mice. Cardiovasc Res. 72:134–142. 2006. View Article : Google Scholar : PubMed/NCBI
9	Zhu H, Shan L, Schiller PW, Mai A and Peng T: Histone deacetylase-3 activation promotes tumor necrosis factor-alpha (TNF-α) expression in cardiomyocytes during lipopolysaccharide stimulation. J Biol Chem. 285:9429–9436. 2010. View Article : Google Scholar : PubMed/NCBI
10	Adamopoulos S, Parissis JT and Kremastinos DT: A glossary of circulating cytokines in chronic heart failure. Eur J Heart Fail. 3:517–526. 2001. View Article : Google Scholar : PubMed/NCBI
11	Collins T, Read MA, Neish AS, Whitley MZ, Thanos D and Maniatis T: Transcriptional regulation of endothelial cell adhesion molecules: NF-κB and cytokine-inducible enhancers. FASEB J. 9:899–909. 1995.PubMed/NCBI
12	Fischer E, Van Zee KJ, Marano MA, et al: Interleukin-1 receptor antagonist circulates in experimental inflammation and in human disease. Blood. 79:2196–2200. 1992.PubMed/NCBI
13	Ceylan-Isik AF, Zhao P, Zhang B, Xiao X, Su G and Ren J: Cardiac overexpression of metallothionein rescues cardiac contractile dysfunction and endoplasmic reticulum stress but not autophagy in sepsis. J Mol Cell Cardiol. 48:367–378. 2010. View Article : Google Scholar :
14	Peng T, Lu X, Lei M, Moe GW and Feng Q: Inhibition of p38 MAPK decreases myocardial TNF-α expression and improves myocardial function and survival in endotoxemia. Cardiovasc Res. 59:893–900. 2003. View Article : Google Scholar : PubMed/NCBI
15	van Empel VP, Bertrand AT, Hofstra L, Crijns HJ, Doevendans PA and De Windt LJ: Myocyte apoptosis in heart failure. Cardiovasc Res. 67:21–29. 2005. View Article : Google Scholar : PubMed/NCBI
16	Hale SL, Birnbaum Y and Kloner RA: Estradiol, administered acutely, protects ischemic myocardium in both female and male rabbits. J Cardiovasc Pharmacol Ther. 2:47–52. 1997. View Article : Google Scholar : PubMed/NCBI
17	Baker L, Meldrum KK, Wang M, et al: The role of estrogen in cardiovascular disease. J Surg Res. 115:325–344. 2003. View Article : Google Scholar : PubMed/NCBI
18	Ylikorkala O: HRT as secondary prevention of cardiovascular disease. Maturitas. 47:315–318. 2004. View Article : Google Scholar : PubMed/NCBI
19	Schröder J, Kahlke V, Staubach KH, Zabel P and Stuber F: Gender differences in human sepsis. Arch Surg. 133:1200–1205. 1998. View Article : Google Scholar : PubMed/NCBI
20	Usui T: Pharmaceutical prospects of phytoestrogens. Endocr J. 53:7–20. 2006. View Article : Google Scholar : PubMed/NCBI
21	Zhang HS and Wang SQ: Notoginsenoside R1 inhibits TNF-α-induced fibronectin production in smooth muscle cells via the ROS/ERK pathway. Free Radic Biol Med. 40:1664–1674. 2006. View Article : Google Scholar : PubMed/NCBI
22	Sun K, Wang CS, Guo J, et al: Protective effects of ginsenoside Rb1, ginsenoside Rg1, and notoginsenoside R1 on lipopolysaccharide-induced microcirculatory disturbance in rat mesentery. Life Sci. 81:509–518. 2007. View Article : Google Scholar : PubMed/NCBI
23	Zhang WJ, Wojta J and Binder BR: Notoginsenoside R1 counteracts endotoxin-induced activation of endothelial cells in vitro and endotoxin-induced lethality in mice in vivo. Arterioscler Thromb Vasc Biol. 17:465–474. 1997. View Article : Google Scholar : PubMed/NCBI
24	Baeuerle PA and Henkel T: Function and activation of nf-κb in the immune system. Annu Rev Immunol. 12:141–179. 1994. View Article : Google Scholar
25	Lennikov A, Kitaichi N, Noda K, et al: Amelioration of endotoxin-induced uveitis treated with an iκb kinase β inhibitor in rats. Mol Vis. 18:2586–2597. 2012.
26	Zandi E, Chen Y and Karin M: Direct phosphorylation of IkappaB by IKKα and IKKβ: discrimination between free and NF-κB-bound substrate. Science. 281:1360–1363. 1998. View Article : Google Scholar : PubMed/NCBI
27	Carlson DL, Willis MS, White DJ, Horton JW and Giroir BP: Tumor necrosis factor-α-induced caspase activation mediates endotoxin-related cardiac dysfunction. Crit Care Med. 33:1021–1028. 2005. View Article : Google Scholar : PubMed/NCBI
28	Tatsumi T, Akashi K, Keira N, et al: Cytokine-induced nitric oxide inhibits mitochondrial energy production and induces myocardial dysfunction in endotoxin-treated rat hearts. J Mol Cell Cardiol. 37:775–784. 2004. View Article : Google Scholar : PubMed/NCBI
29	Brinckmann M, Kaschina E, Altarche-Xifró W, et al: Estrogen receptor α supports cardiomyocytes indirectly through post-infarct cardiac c-kit+ cells. J Mol Cell Cardiol. 47:66–75. 2009. View Article : Google Scholar : PubMed/NCBI
30	Wu CH, Liu JY, Wu JP, et al: et al 17β-estradiol reduces cardiac hypertrophy mediated through the up-regulation of PI3K/Akt and the suppression of calcineurin/NF-AT3 signaling pathways in rats. Life Sci. 78:347–356. 2005. View Article : Google Scholar : PubMed/NCBI
31	Murphy E: Estrogen signaling and cardiovascular disease. Circ Res. 109:687–696. 2011. View Article : Google Scholar : PubMed/NCBI
32	Xi YD, Yu HL, Ding J, et al: Flavonoids protect cerebrovascular endothelial cells through Nrf2 and PI3K from β-amyloid peptide-induced oxidative damage. Curr Neurovasc Res. 9:32–41. 2012. View Article : Google Scholar : PubMed/NCBI
33	Sun B, Xiao J, Sun XB and Wu Y: Notoginsenoside R1 attenuates cardiac dysfunction in endotoxemic mice: an insight into oestrogen receptor activation and PI3K/Akt signalling. Br J Pharmacol. 168:1758–1770. 2013. View Article : Google Scholar :
34	Xiao J, Wang NL, Sun B and Cai GP: Estrogen receptor mediates the effects of pseudoprotodiocsin on adipogenesis in 3T3-L1 cells. Am J Physiol Cell Physiol. 299:C128–C138. 2010. View Article : Google Scholar : PubMed/NCBI