Insights into the Molecular Mechanisms of Lithium on Cardioprotection in Social Stress (1/2)

Cardiovascular disease is among the leading causes resulting in the excessive and premature deaths in patients with bipolar disorder. Emerging evidence suggests that lithium may reduce cardiovascular morbidity and mortality in patients with bipolar disorder. Cardiac fibrosis plays a
vital role in the pathogenesis of heart failure. However, little is known about whether lithium at therapeutic levels exert cardioprotective effect via its anti-fibrotic function. Besides, few studies have investigated the underlying mechanisms for anti-fibrotic actions of therapeutic lithium. In this project, we performed migration and proliferation assays, western blotting, realtime reverse-transcription polymerase chain reaction analysis, and calcium fluorescence imaging in human cardiac fibroblasts treated with or without LiCl at 1.0 mM (i.e., therapeutic peak level) or 0.1 mM (i.e., therapeutic trough
level) for 24 hours. Results showed that LiCl (0.1 mM) inhibited the migration and collagen synthesis ability of cardiac fibroblasts. In addition, thapsigargin-induced store-operated Ca2+ entry (SOCE) was reduced in fibroblasts treated with LiCl (0.1 mM). The expression level of Orai1
was lower in LiCl (0.1 mM)-treated fibroblasts relative to the fibroblasts without LiCl treatment. Fibroblasts treated with a combination of LiCl (0.1 mM) and 2-APB (10 μM, an Orai1 inhibitor) demonstrated similar migration and collagen synthesis abilities as those in LiCl (0.1 mM)- treated fibroblasts. Altogether, our study illustrated that lithium at therapeutic trough levels reduced the migration and collagen synthesis abilities of human cardiac
fibroblasts by inhibiting SOCE and Orai1 expression. Future translational research is mandatory to investigate the cardioprotective potentials of lithium in patients with bipolar disorder.