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J Clin Med. 2019 Jun 20;8(6). pii: E881. doi: 10.3390/jcm8060881.

Very Low-Density Lipoproteins of Metabolic Syndrome Modulates STIM1, Suppresses Store-Operated Calcium Entry, and Deranges Myofilament Proteins in Atrial Myocytes.

Shiou YL1,2,3, Lin HT4, Ke LY5,6, Wu BN7, Shin SJ8, Chen CH9,10, Tsai WC11,12, Chu CS13,14,15, Lee HC16,17,18,19,20.

Author information

1
Center for Lipid Biosciences, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. irpu10.yls@gmail.com.
2
Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan. irpu10.yls@gmail.com.
3
Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan. irpu10.yls@gmail.com.
4
Center for Lipid Biosciences, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. hsintinglin2007@gmail.com.
5
Center for Lipid Biosciences, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. thwangg@gmail.com.
6
Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan. thwangg@gmail.com.
7
Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. binnan@gap.kmu.edu.tw.
8
Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. sjshin@kmu.edu.tw.
9
Center for Lipid Biosciences, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. cchen@heart.thi.tmc.edu.
10
Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan. cchen@heart.thi.tmc.edu.
11
Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan. azygo91@gmail.com.
12
Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. azygo91@gmail.com.
13
Center for Lipid Biosciences, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. jujuson993@gmail.com.
14
Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan. jujuson993@gmail.com.
15
Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. jujuson993@gmail.com.
16
Center for Lipid Biosciences, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. hclee@kmu.edu.tw.
17
Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan. hclee@kmu.edu.tw.
18
Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan. hclee@kmu.edu.tw.
19
Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. hclee@kmu.edu.tw.
20
Institute/Center of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung 807, Taiwan. hclee@kmu.edu.tw.

Abstract

Individuals with metabolic syndrome (MetS) are at high risk for atrial myopathy and atrial fibrillation. Very low-density lipoproteins (VLDLs) of MetS (MetS-VLDLs) are cytotoxic to atrial myocytes in vivo and in vitro. The calcineurin-nuclear factor of activated T-cells (NFAT) pathway, which is regulated by stromal interaction molecule 1 (STIM1)/ calcium release-activated calcium channel protein 1 (Orai1)-mediated store-operated Ca2+ entry (SOCE), is a pivotal mediator of adaptive cardiac hypertrophy. We hypothesized that MetS-VLDLs could affect SOCE and the calcineurin-NFAT pathway. Normal-VLDL and MetS-VLDL samples were isolated from the peripheral blood of healthy volunteers and individuals with MetS. VLDLs were applied to HL-1 atrial myocytes for 18 h and were also injected into wild-type C57BL/6 male mouse tails three times per week for six weeks. After the sarcoplasmic reticulum (SR) Ca2+ store was depleted, SOCE was triggered upon reperfusion with 1.8 mM of Ca2+. SOCE was attenuated by MetS-VLDLs, along with reduced transcriptional and membranous expression of STIM1 (P = 0.025), and enhanced modification of O-GlcNAcylation on STIM1 protein, while Orai1 was unaltered. The nuclear translocation and activity of calcineurin were both reduced (P < 0.05), along with the alteration of myofilament proteins in atrial tissues. These changes were absent in normal-VLDL-treated cells. Our results demonstrated that MetS-VLDLs suppressed SOCE by modulating STIM1 at the transcriptional, translational, and post-translational levels, resulting in the inhibition of the calcineurin-NFAT pathway, which resulted in the alteration of myofilament protein expression and sarcomere derangement in atrial tissues. These findings may help explain atrial myopathy in MetS. We suggest a therapeutic target on VLDLs to prevent atrial fibrillation, especially for individuals with MetS.

KEYWORDS:

SOCE; STIM1; atrial fibrillation; atrial myopathy; metabolic syndrome; very low-density lipoprotein

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