Sulodexide Attenuates Endoplasmic Reticulum Stress Induced by Myocardial Ischaemia/reperfusion by Activating the PI3K/Akt Pathway

Overview

Journal J Cell Mol Med

Specialties Cell Biology
Molecular Biology

Date 2019 May 24

PMID 31120192

Citations 27

Authors

Danping Shen

Ruiyao Chen

Lijing Zhang

Zhiheng Rao

Yongxue Ruan

Lei Li

Maoping Chu

Yuanhai Zhang

Affiliations

Soon will be listed here.

Abstract

Acute myocardial ischaemia/reperfusion (MI/R) injury causes severe arrhythmias with a high rate of lethality. Extensive research focus on endoplasmic reticulum (ER) stress and its dysfunction which leads to cardiac injury in MI/R Our study evaluated the effects of sulodexide (SDX) on MI/R by establishing MI/R mice models and in vitro oxidative stress models in H9C2 cells. We found that SDX decreases cardiac injury during ischaemia reperfusion and decreased myocardial apoptosis and infarct area, which was paralleled by increased superoxide dismutase and reduced malondialdehyde in mice plasm, increased Bcl-2 expression, decreased BAX expression in a mouse model of MI/R. In vitro, SDX exerted a protective effect by the suppression of the ER stress which induced by tert-butyl hydroperoxide (TBHP) treatment. Both of the in vivo and in vitro effects were involved in the phosphatidylinositol 3-kinase (PI3K)/Akt signalling pathway. Inhibition of PI3K/Akt pathway by specific inhibitor, LY294002, partially reduced the protective effect of SDX. In short, our results suggested that the cardioprotective role of SDX was related to the suppression of ER stress in mice MI/R models and TBHP-induced H9C2 cell injury which was through the PI3K/Akt signalling pathway.

Citing Articles

The Preventive and Therapeutic Effects of Acute and Severe Inflammatory Disorders with Heparin and Heparinoid.

Song Y, Wu Y, Ding F, Li S, Shen Y, Yang B Biomolecules. 2024; 14(9).

PMID: 39334845 PMC: 11430252. DOI: 10.3390/biom14091078.

Peroxiredoxin II exerts neuroprotective effects by inhibiting endoplasmic reticulum stress and oxidative stress-induced neuronal pyroptosis.

Jin M, Liu X, Sun H, Han Y, Kwon T Mol Biol Rep. 2024; 51(1):607.

PMID: 38704801 DOI: 10.1007/s11033-024-09568-5.

Screening and identification of effective components from modified Taohong Siwu decoction for protecting H9c2 cells from damage.

Wang Y, Wang H, Shao C, Li X, Cui J, Guo H In Vitro Cell Dev Biol Anim. 2023; 59(5):346-355.

PMID: 37294373 DOI: 10.1007/s11626-023-00773-3.

Leptin alleviates endoplasmic reticulum stress induced by cerebral ischemia/reperfusion injury via the PI3K/Akt signaling pathway.

Zhang Y, Cheng D, Jie C, Liu T, Huang S, Hu S Biosci Rep. 2022; 42(12).

PMID: 36367210 PMC: 9744719. DOI: 10.1042/BSR20221443.

Sulodexide Increases Glutathione Synthesis and Causes Pro-Reducing Shift in Glutathione-Redox State in HUVECs Exposed to Oxygen-Glucose Deprivation: Implication for Protection of Endothelium against Ischemic Injury.

Bontor K, Gabryel B Molecules. 2022; 27(17).

PMID: 36080234 PMC: 9457652. DOI: 10.3390/molecules27175465.

References

Yang C . Clinical manifestations and basic mechanisms of myocardial ischemia/reperfusion injury. Tzu Chi Med J. 2018; 30(4):209-215. PMC: 6172894. DOI: 10.4103/tcmj.tcmj_33_18. View

Wu H, Ye M, Yang J, Ding J, Yang J, Dong W . Nicorandil Protects the Heart from Ischemia/Reperfusion Injury by Attenuating Endoplasmic Reticulum Response-induced Apoptosis Through PI3K/Akt Signaling Pathway. Cell Physiol Biochem. 2015; 35(6):2320-32. DOI: 10.1159/000374035. View

Ibanez B, Heusch G, Ovize M, Van de Werf F . Evolving therapies for myocardial ischemia/reperfusion injury. J Am Coll Cardiol. 2015; 65(14):1454-71. DOI: 10.1016/j.jacc.2015.02.032. View

Tiozzo R, Cingi M, Pietrangelo A, Albertazzi L, Calandra S, Milani M . Effect of heparin-like compounds on the in vitro proliferation and protein synthesis of various cell types. Arzneimittelforschung. 1989; 39(1):15-20. View

Yin J, Chen W, Ma F, Lu Z, Wu R, Zhang G . Sulodexide pretreatment attenuates renal ischemia-reperfusion injury in rats. Oncotarget. 2016; 8(6):9986-9995. PMC: 5354786. DOI: 10.18632/oncotarget.14309. View

Mao W, Iwai C, Liu J, Sheu S, Fu M, Liang C . Darbepoetin alfa exerts a cardioprotective effect in autoimmune cardiomyopathy via reduction of ER stress and activation of the PI3K/Akt and STAT3 pathways. J Mol Cell Cardiol. 2008; 45(2):250-60. PMC: 2599925. DOI: 10.1016/j.yjmcc.2008.05.010. View

Andriuoli G, Mastacchi R, Barbanti M . Antithrombotic activity of a glycosaminoglycan (sulodexide) in rats. Thromb Res. 1984; 34(1):81-6. DOI: 10.1016/0049-3848(84)90108-7. View

Zhou H, Sun Q, Cheng Y . Paeonol enhances the sensitivity of human ovarian cancer cells to radiotherapy-induced apoptosis due to downregulation of the phosphatidylinositol-3-kinase/Akt/phosphatase and tensin homolog pathway and inhibition of vascular endothelial growth.... Exp Ther Med. 2017; 14(4):3213-3220. PMC: 5585758. DOI: 10.3892/etm.2017.4877. View

Friedrichs G, Kilgore K, Manley P, Gralinski M, Lucchesi B . Effects of heparin and N-acetyl heparin on ischemia/reperfusion-induced alterations in myocardial function in the rabbit isolated heart. Circ Res. 1994; 75(4):701-10. DOI: 10.1161/01.res.75.4.701. View

10.

Crepaldi G, Rossi A, Coscetti G, Abbruzzese E, Calveri U, Calabro A . Sulodexide oral administration influences blood viscosity and fibrinolysis. Drugs Exp Clin Res. 1992; 18(5):189-95. View

11.

Corsi C, Bocci L, Cipriani C, Gazzini A, Marrapodi E . The effectiveness of glycosaminoglycans in peripheral vascular disease therapy: a clinical and experimental trial. J Int Med Res. 1985; 13(1):40-7. DOI: 10.1177/030006058501300106. View

12.

Coccheri S, Mannello F . Development and use of sulodexide in vascular diseases: implications for treatment. Drug Des Devel Ther. 2014; 8:49-65. PMC: 3879015. DOI: 10.2147/DDDT.S6762. View

13.

Hausenloy D, Yellon D . New directions for protecting the heart against ischaemia-reperfusion injury: targeting the Reperfusion Injury Salvage Kinase (RISK)-pathway. Cardiovasc Res. 2004; 61(3):448-60. DOI: 10.1016/j.cardiores.2003.09.024. View

14.

Mannello F, Ligi D, Raffetto J . Glycosaminoglycan sulodexide modulates inflammatory pathways in chronic venous disease. Int Angiol. 2014; 33(3):236-42. View

15.

Wolfrum S, Dendorfer A, Rikitake Y, Stalker T, Gong Y, Scalia R . Inhibition of Rho-kinase leads to rapid activation of phosphatidylinositol 3-kinase/protein kinase Akt and cardiovascular protection. Arterioscler Thromb Vasc Biol. 2004; 24(10):1842-7. PMC: 2649731. DOI: 10.1161/01.ATV.0000142813.33538.82. View

16.

Sardao V, Oliveira P, Holy J, Oliveira C, Wallace K . Vital imaging of H9c2 myoblasts exposed to tert-butylhydroperoxide--characterization of morphological features of cell death. BMC Cell Biol. 2007; 8:11. PMC: 1831770. DOI: 10.1186/1471-2121-8-11. View

17.

Forouzanfar M, Moran A, Flaxman A, Roth G, Mensah G, Ezzati M . Assessing the global burden of ischemic heart disease, part 2: analytic methods and estimates of the global epidemiology of ischemic heart disease in 2010. Glob Heart. 2013; 7(4):331-342. PMC: 3595103. DOI: 10.1016/j.gheart.2012.10.003. View

18.

Chouchani E, Pell V, Gaude E, Aksentijevic D, Sundier S, Robb E . Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature. 2014; 515(7527):431-435. PMC: 4255242. DOI: 10.1038/nature13909. View

19.

Wang X, Fu Y, Liu X, Feng G, Xiong D, Mu G . ROS Promote Ox-LDL-Induced Platelet Activation by Up-Regulating Autophagy Through the Inhibition of the PI3K/AKT/mTOR Pathway. Cell Physiol Biochem. 2018; 50(5):1779-1793. DOI: 10.1159/000494795. View

20.

Gralinski M, Park J, Ozeck M, Wiater B, Lucchesi B . LU 51198, a highly sulfated, low-molecular-weight heparin derivative, prevents complement-mediated myocardial injury in the perfused rabbit heart. J Pharmacol Exp Ther. 1997; 282(2):554-60. View