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Resveratrol pretreatment alleviates myocardial ischemia/reperfusion injury by inhibiting STIM1-mediated intracellular calcium accumulation

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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.

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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

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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).

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Author notes

  1. Han Xu and Jing Cheng  contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiology, Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China

    Han Xu, Jixiong Wu, Banglong Xu & Fei He

  2. Clinical Medical College of Anhui Medical University, Hefei, Anhui, China

    Han Xu

  3. School of Nursing, Anhui University of Traditional Chinese Medicine, No.103 of Middle Meishan Road, Hefei, Anhui, China

    Jing Cheng

  4. Department of Cardiology, Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China

    Xianbao Wang, Haiqiong Liu, Siyi Wang & Aihua Chen

  5. Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Guangzhou, Guangdong, China

    Xianbao Wang, Haiqiong Liu, Siyi Wang & Aihua Chen

  6. Sino-Japanese Cooperation Platform for Translational Research in Heart Failure, Guangzhou, Guangdong, China

    Xianbao Wang, Haiqiong Liu, Siyi Wang & Aihua Chen

  7. Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China

    Xianbao Wang, Haiqiong Liu, Siyi Wang & Aihua Chen

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  1. Han Xu
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Correspondence to Aihua Chen or Fei He.

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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

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  • DOI: https://doi.org/10.1007/s13105-019-00704-5

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