The role of Stearate in the regulation of vascular calcification in chronic kidne

描述（由申请人提供）：心血管疾病如血管钙化是CKD患者死亡的主要原因。然而，目前尚无有效的治疗血管钙化的方法。硬脂酸盐是哺乳动物细胞中的一种主要饱和脂肪酸，通过两种途径获得：膳食脂肪吸收和脂肪新生。我们的长期目标是确定预防血管钙化的新药理学策略。我们之前的研究表明，从脂肪生成中提取的硬脂酸盐促进主动脉钙化。硬脂酰辅酶a去饱和酶(SCD)-1和SCD2都是参与硬脂酸代谢的中心酶。正如我们的初步结果所示，通过添加外源性硬脂酸盐或抑制SCD1和SCD2来增加硬脂酸盐，可以增强体外和体内血管钙化。最近，我们发现血清硬脂酸盐水平显著增加

DESCRIPTION (provided by applicant): 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.