ER stress conditions lead to an upregulation of TFPI and is associated with an anti-apoptotic macrophage phenotype

Endoplasmic reticulum (ER) stress is an important event during the initiation and clinical progression of several cardiovascular diseases, including atherosclerosis. In the present study we determined the role of tissue factor pathway inhibitor (TFPI) under ER stress conditions using human monocyte-derived macrophages (PBMC) and human carotid endarterectomies. TFPI was expressed in carotid plaques from patients with internal carotid stenosis, especially the TFPIα isoform. Moreover, TFPI colocalized with the ER stress marker CHOP in the plaques. Cholesterol crystals (CC) were used in human M1 and M2-polarized macrophages in vitro as an inducer of ER stress. CHOP and TFPI mRNA levels were upregulated after CC treatment, especially in the M2 phenotype. The ER stress inhibitor 4-Phenylbutyric acid (PBA) reversed the CC-mediated upregulation of CHOP and TFPI. Furthermore, M2-polarized macrophages incubated with CC had higher levels of Bcl-2:Bax mRNA ratios and Bcl-2 protein expression, and these effects were reversed by TFPI knockdown and PBA treatment. Our results indicate that TFPI could promote survival of the M2-polarized macrophages under ER stress conditions. These findings may have implications for the pathogenesis of atherosclerosis.