Cardiovascular disease such as vascular calcification is a leading cause of death in subjects with CKD. However, there is no effective therapy for vascular calcification available. Stearate, a major saturated fatty acid in mammalian cells, is derived through two pathways: dietary fat absorption and de novo lipogenesis. Our long-term goal is to identify new pharmacological strategies for the prevention of vascular calcification. Our previous study has revealed that stearate derived from de novo lipogenesis promotes aortic calcification. Both stearoyl-CoA desaturase (SCD)-1 and SCD2 are central enzymes involved in the metabolism of stearic acid. As shown in our preliminary results, increasing stearate by adding exogenous stearate or by inhibiting SCD1 and SCD2 augmented vascular calcification in vitro and in vivo. Recently, we found that levels of serum stearate were significantly increased in subjects with chronic kidney disease (CKD), due to lower SCD activity. The pro-calcific and pro-osteogenic effects of stearate were highly correlated with levels of distearoyl-phosphatidic acid (18:0-PA) in the ER and the expression of ATF4, which is a central transcription factor in the regulation of osteogenesis. These effects were also associated with the expression of CHOP, a transcription factor that promotes apoptosis. We therefore hypothesize that 18:0-PA derived from stearate synthesized by SCD in the endoplasmic reticulum induces vascular osteogenesis and calcification by activating the PERK-eIF2?-ATF4-CHOP pathway of the unfolded protein response in vivo. We will design experiments to address this hypothesis using in vivo and in vitro approaches. The two specific aims of this proposal are 1) To determine the molecular mechanism underlying stearate-mediated vascular calcification in vitro, and 2) To determine whether the activation of the ATF4-CHOP pathway mediates vascular calcification induced by increased stearate due to VSMC deficiency of SCD1 and SCD2 in vivo.
Vascular calcification is a major cause of death in patients with chronic kidney disease (CKD) who have higher levels of serum stearate. We recently found that vascular calcification is promoted by stearate, one of the major fatty acids found in humans. This research will enhance our understanding of the molecular mechanisms by which stearate promotes vascular calcification.
|Miyazaki-Anzai, Shinobu; Masuda, Masashi; Levi, Moshe et al. (2014) Dual activation of the bile acid nuclear receptor FXR and G-protein-coupled receptor TGR5 protects mice against atherosclerosis. PLoS One 9:e108270|