Abstract
Previous studies have shown that stromal interaction molecule1 (STIM1)-mediated store-operated Ca2+ entry (SOCE) contributes to intracellular Ca2+ accumulation in H9C2 cells subjected to hypoxia/reoxygenation(H/R) injury. The aim of the present study was to investigate the effect of resveratrol on STIM1-mediated intracellular Ca2+ accumulation and subsequent cell death in the context of myocardial ischemia/reperfusion (I/R) injury. C57 BL/6 mice were fed with either saline or resveratrol (50 mg/kg daily for 2 weeks) and then subjected to myocardial I/R injury. TTC/Evans Blue staining and TUNEL assay were performed to quantify the infarct size and apoptosis index. The cardiac function was evaluated by echocardiography. Neonatal rat ventricular cardiomyocytes (NRVCs) underwent hypoxia/reoxygenation (H/R) to establish the in vitro model. To achieve over-expression, NRVCs were transfected with STIM1-adenovirus vector. Apoptosis was analyzed by TUNEL assay. Cell viability was measured using MTS assay and cell necrosis was determined by LDH release assay. Intracellular Ca2+ concentration was detected by laser scanning confocal microscopy using a Fluo-3AM probe. Resveratrol significantly reduced apoptosis, decreased infarct size, and improved cardiac function in mice subjected to myocardial I/R injury. In NRVCs, resveratrol also downregulated STIM1 expression accompanied by decreased intracellular Ca2+ accumulation elicited by H/R injury. In addition, resveratrol reduced cell apoptosis, upregulated the Bcl-2, decreased Bax, and cleaved caspase-3 expression. Furthermore, the effects of resveratrol on STIM1-mediated intracellular Ca2+ accumulation, apoptotic proteins, and H/R-induced cell injury were exacerbated by STIM1 over-expression and were partly abolished by SOCE inhibitor SKF96365 in NRVCs in vitro. Our findings demonstrate that resveratrol exerts anti-apoptotic activity and improves cardiac functional recovery following myocardial I/R by inhibiting STIM1-induced intracellular Ca2+ accumulation.
Similar content being viewed by others
Abbreviations
- AAR:
-
Area at risk
- PCI:
-
Percutaneous coronary intervention
- NCX:
-
Na+-Ca2+ exchanger
- ACS:
-
Acute coronary syndrome
- AMI:
-
Acute myocardial infarction
- STEMI:
-
ST segment elevation myocardial infarction
- SOCE:
-
Store-operated calcium channels
- STIM:
-
stromal interaction molecule
- RSV:
-
Trans-3,4′,5-trihydroxystilbene
- I/R:
-
Ischemia/reperfusion
- DMEM:
-
Dulbecco’s modified Eagle’s medium
- FBS:
-
Fetal bovine serum
References
Heusch G, Gersh BJ (2017) The pathophysiology of acute myocardial infarction and strategies of protection beyond reperfusion: a continual challenge. Eur Heart J 38:774–784. https://doi.org/10.1093/eurheartj/ehw224
Correll RN, Goonasekera SA, van Berlo JH, Burr AR, Accornero F, Zhang H, Makarewich CA, York AJ, Sargent MA, Chen X, Houser SR, Molkentin JD (2015) STIM1 elevation in the heart results in aberrant Ca2 + handling and cardiomyopathy. J Mol Cell Cardiol 87:38–47. https://doi.org/10.1016/j.yjmcc.2015.07.032
Garcia-Dorado D, Ruiz-Meana M, Inserte J, Rodriguez-Sinovas A, Piper HM (2012) Calcium-mediated cell death during myocardial reperfusion. Cardiovasc Res 94:168–180. https://doi.org/10.1093/cvr/cvs116
Ibanez B, Heusch G, Ovize M, Van de Werf F (2015) Evolving therapies for myocardial ischemia/reperfusion injury. J Am Coll Cardiol 65:1455–1471
Qian CP, Ma JH, Zhang PH, Luo AT, Wang C, Ren ZQ, Kong LH, Zhang S, Wang XJ, Wu Y (2012) Resveratrol attenuates the Na+−dependent intracellular Ca2+ overload by inhibiting H2O2-induced increase in late sodium current in ventricular myocytes. PLoS One 7:e51358. https://doi.org/10.1371/journal.pone.0051358
Ambudkar IS, de Souza LB, Ong HL (2017) TRPC1, Orai1, and STIM1 in SOCE: friends in tight spaces. Cell Calcium 63:33–39. https://doi.org/10.1016/j.ceca.2016.12.009
Hausenloy DJ, Yellon DM (2016) Ischaemic conditioning and reperfusion injury. Nat Rev Cardiol 13:193–209. https://doi.org/10.1038/nrcardio.2016.5
Voelkers M, Salz M, Herzog N, Frank D, Dolatabadi N, Frey N, Gude N, Friedrich O, Koch WJ, Katus HA, Sussman MA, Most P (2010) Orai1 and Stim1 regulate normal and hypertrophic growth in cardiomyocytes. J Mol Cell Cardiol 48:1329–1334. https://doi.org/10.1016/j.yjmcc.2010.01.020
Ayub A, Poulose N, Raju R (2015) Resveratrol improves survival and prolongs life following hemorrhagic shock. Mol Med 21(1):305–312. https://doi.org/10.2119/molmed.2015.00013
Wang B, Yang Q, Y-y S, Y-f X, Y-b W, X-t L, W-w B, X-q L, Y-x Z (2014) Resveratrol-enhanced autophagic flux ameliorates myocardial oxidative stress injury in diabetic mice. J Cell Mol Med 18:1599–1611. https://doi.org/10.1111/jcmm.12312
Yang L, Zhang Y, Zhu MM, Zhang Q, Wang XL, Wang YJ, Zhang JC, Li J, Yang L, Liu J, Liu F, Yang YA, Kang LC, Shen YN, Qi Z (2016) Resveratrol attenuates myocardial ischemia/reperfusion injury through up-regulation of vascular endothelial growth factor B. Free Radical Bio Med 101:1–9. https://doi.org/10.1016/j.freeradbiomed.2016.09.016
Madsen CP, Klausen TK, Fabian A, Hansen BJ, Pedersen SF, Hoffmann EK (2012) On the role of TRPC1 in control of Ca2+ influx, cell volume, and cell cycle. Am J Phys Cell Phys 303:C625–C634. https://doi.org/10.1152/ajpcell.00287.2011
Benard L, Oh JG, Cacheux M, Lee A, Nonnenmacher M, Matasic DS, Kohlbrenner E, Kho C, Pavoine C, Hajjar RJ, Hulot JS (2016) Cardiac Stim1 silencing impairs adaptive hypertrophy and promotes heart failure through inactivation of mTORC2/Akt signaling. Circulation 133:1458–1471. https://doi.org/10.1161/circulationaha.115.020678
Lopez JJ, Albarran L, Gomez LJ, Smani T, Salido GM, Rosado JA (2016) Molecular modulators of store-operated calcium entry. Biochim Biophys Acta-Mol Cell Res 1863:2037–2043. https://doi.org/10.1016/j.bbamcr.2016.04.024
Sasamori J, Hasegawa T, Takaya A, Watanabe Y, Tanaka M, Ogino Y, Chiba T, Aihara K (2014) The cardioprotective effects of novel Na+/H+ exchanger inhibitor TY-51924 on ischemia/reperfusion injury. J Cardiovasc Pharmacol 63:351–359. https://doi.org/10.1097/FJC.0000000000000055
He F, Wu Q, Xu B, Wang X, Wu J, Huang L, Cheng J (2017) Suppression of Stim1 reduced intracellular calcium concentration and attenuated hypoxia/reoxygenation induced apoptosis in H9C2 cells. Biosci Rep 37. https://doi.org/10.1042/bsr20171249
Liao Z, Liu D, Tang L, Yin D, Yin S, Lai S, Yao J, He M (2015) Long-term oral resveratrol intake provides nutritional preconditioning against myocardial ischemia/reperfusion injury: involvement of VDAC1 downregulation. Mol Nutr Food Res 59:454–464. https://doi.org/10.1002/mnfr.201400730
Casas-Rua V, Alvarez IS, Pozo-Guisado E, Martin-Romero FJ (2013) Inhibition of STIM1 phosphorylation underlies resveratrol-induced inhibition of store-operated calcium entry. Biochem Pharmacol 86:1555–1563. https://doi.org/10.1016/j.bcp.2013.09.018
Kojima A, Kitagawa H, Omatsu-Kanbe M, Matsuura H, Nosaka S (2012) Presence of store-operated Ca-2 entry in C57BL/6J mouse ventricular myocytes and its suppression by sevoflurane. Br J Anaesth 109:352–360. https://doi.org/10.1093/bja/aes212
Halestrap AP, Clarke SJ, Javadov SA (2004) Mitochondrial permeability transition pore opening during myocardial reperfusion - a target for cardioprotection. Cardiovasc Res 61:372–385. https://doi.org/10.1016/s0008-6363(03)00533-9
Imahashi K, Pott C, Goldhaber JI, Steenbergen C, Philipson KD, Murphy E (2005) Cardiac-specific ablation of the Na+-Ca2+ exchanger confers protection against ischemia/reperfusion injury. Circ Res 97:916–921. https://doi.org/10.1161/01.RES.0000187456.06162.cb
He F, Xu BL, Chen C, Jia HJ, Wu JX, Wang XC, Sheng JL, Huang L, Cheng J (2016) Methylophiopogonanone A suppresses ischemia/reperfusion-induced myocardial apoptosis in mice via activating PI3K/Akt/eNOS signaling pathway. Acta Pharmacol Sin 37:763–771. https://doi.org/10.1038/aps.2016.14
Javadov S, Choi A, Rajapurohitam V, Zeidan A, Basnakian AG, Karmazyn M (2008) NHE-1 inhibition-induced cardioprotection against ischaemia/reperfusion is associated with attenuation of the mitochondrial permeability transition. Cardiovasc Res 77:416–424. https://doi.org/10.1093/cvr/cvm039
Selvaraj S, Sun Y, Sukumaran P, Singh BB (2016) Resveratrol activates autophagic cell death in prostate cancer cells via downregulation of STIM1 and the mTOR pathway. Mol Carcinog 55:818–831. https://doi.org/10.1002/mc.22324
Cheng J, Wu Q, Lv R, Huang L, Xu B, Wang X, Chen A, He F (2018) MicroRNA-449a inhibition protects H9C2 cells against hypoxia/reoxygenation-induced injury by targeting the notch-1 signaling pathway. Cell Physiol Biochem 46:2587–2600. https://doi.org/10.1159/000489686
Ling YN, Chen GM, Deng Y, Tang HX, Ling L, Zhou XM, Song XD, Yang PZ, Liu YF, Li ZL, Zhao C, Yang YF, Wang XB, Kitakaze M, Liao YL, Chen AH (2016) Polydatin post-treatment alleviates myocardial ischaemia/reperfusion injury by promoting autophagic flux. Clin Sci 130:1641–1653. https://doi.org/10.1042/cs20160082
Collins HE, Zhu-Mauldin X, Marchase RB, Chatham JC (2013) STIM1/orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology. Am J Phys Heart Circ Phys 305:H446–H458. https://doi.org/10.1152/ajpheart.00104.2013
Lu T, Zhou D, Gao P, Si L, Xu Q (2017) Resveratrol attenuates high glucose-induced endothelial cell apoptosis via mediation of store-operated calcium entry. Mol Cell Biochem https://doi.org/10.1007/s11010-017-3194-7. doi:https://doi.org/10.1007/s11010-017-3194-7
Zordoky BN, Robertson IM, Dyck JR (2015) Preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular diseases. Biochim Biophys Acta 1852:1155–1177. https://doi.org/10.1016/j.bbadis.2014.10.016
Funding
This work was supported by the Anhui Provincial Natural Science Foundation (grant no. 1808085QH235 to He Fei), Youth Elites Support Plan in universities of Anhui Province (grant no. gxyq2019013 to He Fei), Science and Technology New Star Program of Second affiliated Hospital of Anhui Medical University (grant no. 2018KA06 to He Fei), Key Natural Science Project of Anhui Colleges and Universities (grant no. KJ2018A0284 to Cheng Jing), Natural Science Foundation of China (grant no. 81903833 to Cheng Jing), and Natural Science Foundation of China (grant no. 81873460 to Chen Aihua).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Xu, H., Cheng, J., Wang, X. et al. Resveratrol pretreatment alleviates myocardial ischemia/reperfusion injury by inhibiting STIM1-mediated intracellular calcium accumulation. J Physiol Biochem 75, 607–618 (2019). https://doi.org/10.1007/s13105-019-00704-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13105-019-00704-5