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.