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.
Highlights
Despite advances in current therapy, the prevention of atrial fibrillation remains a challenge
The effects of Very low-density lipoproteins (VLDLs) on stromal interaction molecule 1 (STIM1) expression were investigated by quantitative RT-PCR and western blot
metabolic syndrome (MetS)-VLDLs significantly reduced STIM1 in HL-1 cells, and the reduction was at both the transcriptional (0.81 ± 0.02-fold versus control, Figure 1a) and the translational levels (0.33 ± 0.03-fold versus control, Figure 1c)
Summary
Despite advances in current therapy, the prevention of atrial fibrillation remains a challenge. The pathogenesis of early atrial myopathy remains unclear. Intracellular Ca2+ homeostasis is critical for normal cellular function, for cardiomyocytes, and may be dysregulated in early atrial myopathy. Store-operated Ca2+ entry (SOCE) is recognized to coexist with voltage-gated Ca2+ channels in cardiomyocytes and, though this is debated, is suggested to contribute to basal Ca2+ homeostasis [2]. A general function of SOCE is to replenish depleted sarcoplasmic reticulum (SR) Ca2+ stores [3]. Several studies have identified the essential role of SOCE in mediating NFAT nuclear translocation to develop cardiac hypertrophy induced either by IP3-generating agonists or by following pressure overload [2,5,6,7]
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