The transcriptional control of vascular calcification in disease

血管钙化等心血管疾病是慢性阻塞性肺疾病患者死亡的主要原因 肾病(CKD)。然而，目前还没有有效的治疗血管钙化的方法。 光毒性和脂毒性是CKD依赖性血管钙化的主要原因。我们的长期合作 目的是确定预防血管钙化的新的药理策略。我们以前的 研究表明，硬脂酸(C18：0)是一种重要的饱和脂肪酸(SFA)。 有助于CKD依赖的血管钙化的代谢物。从机制上讲，CKD介导 高磷血症(高无机磷)诱导VSMC硬脂酰辅酶A显著抑制 去饱和酶(SCD)，是通过将C18：0转化为油酸(C18：1N-)来控制C18：0水平的主要酶。 9)。SCD积聚C18：0强烈诱导VSMCs发生严重的脂毒性，导致血管 钙化。此外，我们的团队还发现，C18：0的促钙化作用主要由两个主要因素介导 通过与甘油-3-磷酸酰基转移酶-4(GPAT4)的酶反应产生C18：0的代谢物： 1)1，2-二硬脂酰磷脂酸(18：0/18：0-PA)，通过活化诱导血管钙化 内质网应激途径的PERK-eIF_2-ATF_4轴和2)1-硬脂酰基-溶磷脂酸(18：0-LPA) 它通过形成异常的MAM相关的omegasome来强烈地抑制自噬通量， 它们是自噬小体形成的平台。C18：0通过激活诱导血管钙化 内质网应激反应和自噬的抑制。然而，潜在的分子机制 CKD介导的高磷血症转录抑制VSMC SCD的上游事件尚未发生 已经研究过了。我们认为，该机制的确定具有治疗潜力。寻找……的线索 在机制方面，我们最近筛选了一个调节表观遗传学和基因转录的化学物库。 基于表观遗传和转录化学文库的筛选，我们鉴定了两个转录 抑制因子候选，有助于磷酸盐介导的SCD抑制和血管钙化。我们 因此，提出了两个特定的目的来阐明脂毒性诱导的上游事件的调节 血管钙化。目标1将检查转录抑制物调制复合体是否影响 通过改变培养细胞中SCD的表达来实现脂毒性和血管钙化。目标2将考察 转录抑制物的调控影响体内的光毒性、脂毒性和血管钙化。 该项目的完成将为CKD介导的血管钙化提供一个新的治疗靶点。

Cardiovascular diseases such as vascular calcification are a leading cause of death in patients with chronic kidney disease (CKD). However, there is no effective therapy for vascular calcification available. Phosphotoxicity and lipototoxicity are the major causes of CKD-dependent vascular calcification. Our long-term goal is to identify new pharmacological strategies for the prevention of vascular calcification. Our previous studies have demonstrated that stearic acid (C18:0), one of the major saturated fatty acids (SFAs), is a critical metabolite that contributes to CKD-dependent vascular calcification. Mechanistically, CKD-mediated hyperphosphatemia (high inorganic phosphate) induces the significant repression of VSMC stearoyl-CoA desaturase (SCD), which is a major enzyme that controls levels of C18:0 by converting it to oleic acid (C18:1n- 9). Accumulation of C18:0 by SCD strongly induces severe lipotoxicity in VSMCs, resulting in vascular calcification. In addition, our group has found that the pro-calcific effect of C18:0 is mediated by two major metabolites of C18:0 generated via the enzyme reaction with glycerol-3-phosphate acyltransferase-4 (GPAT4): 1) 1,2-di-stearoyl-phosphatidic acid (18:0/18:0-PA), which induces vascular calcification through the activation of the PERK-eIF2-ATF4 axis of the ER stress pathway and 2) 1-stearoyl-lysophoshatdic acid (18:0-LPA) which strongly inhibits autophagic flux through the formation of abnormal MAM-associated omegasomes, which are a platform for autophagosome formation. C18:0 induces vascular calcification through the activation of the ER stress response and the inhibition of autophagy. However, the molecular mechanism underlying the upstream event in which CKD-mediated hyperphosphatemia transcriptionally represses VSMC SCD has not been studied. We believe that the identification of the mechanism has therapeutic potentials. To find clues of the mechanism, we recently screened a library of chemicals that modulate epigenetics and gene transcription. Based on the epigenetic and transcriptional chemical library screening, we identified two transcriptional repressor candidates that contribute to phosphate-mediated SCD repression and vascular calcification. We therefore propose two specific aims to elucidate the upstream event in the regulation of lipotoxicity-induced vascular calcification. Aim 1 will examine whether the transcriptional repressor modulation complex affects lipotoxicity and vascular calcification by altering SCD expression in cultured cells. Aim 2 will examine whether modulation of transcriptional repressors affects phosphotoxicity, lipotoxicity and vascular calcification in vivo. Completion of this project will provide a novel therapeutic target for CKD-mediated vascular calcification.