The transcriptional control of vascular calcification in disease

疾病中血管钙化的转录控制

• 批准号: 10647475
• 负责人: Makoto Miyazaki
• 金额: $ 62.61万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10647475
• 关键词: Acids; Acyltransferase; Address; Affect; Aorta; Apoptosis; Autophagocytosis; Autophagosome; Binding; Blood Vessels; Cardiovascular Diseases; Cause of Death; Chronic Kidney Failure; Complex; Cultured Cells; Cyclic AMP-Dependent Protein Kinases; Deacetylation; Dietary Component; Disease; Down-Regulation; Enzymes; Epigenetic Process; Event; Genetic Transcription; Goals; HDAC3 gene; In Vitro; Knockout Mice; Medial; Mediating; Molecular; Mus; Oleic Acids; Pathogenesis; Pathway interactions; Patients; Phosphatidic Acid; Prevention strategy; Production; Reaction; Regulation; Repression; Repressor Proteins; Research; Saturated Fatty Acids; Scheme; Serum; Signal Transduction; Smooth Muscle Myocytes; Stearic Acids; Stearoyl-CoA Desaturase; Therapeutic; Transcription Repressor; Transcriptional Regulation; Vascular Smooth Muscle; Vascular calcification; Work; alpha-glycerophosphoric acid; attenuation; biological adaptation to stress; calcification; coronary artery calcification; effective therapy; endoplasmic reticulum stress; gene repression; human subject; in vivo; inhibition of autophagy; inorganic phosphate; mineralization; mouse model; new therapeutic target; pharmacologic; promoter; screening; small molecule libraries; therapeutic target; transmethylation

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.

心血管疾病如血管钙化是慢性阻塞性肺疾病患者死亡的主要原因。 肾病（CKD）。然而，目前尚无有效的治疗血管钙化的方法。 磷毒性和脂毒性是CKD依赖性血管钙化的主要原因。我们的长期 目的是确定预防血管钙化的新的药理学策略。我们以前的 研究表明，硬脂酸（C18：0），一种主要的饱和脂肪酸（SFA），是一种关键的 代谢产物，导致CKD依赖性血管钙化。机制上，CKD介导 高磷酸盐血症（高无机磷酸盐）诱导VSMC硬脂酰辅酶A的显著抑制 去饱和酶（SCD），其是通过将C18：0转化为油酸（C18：1 n-1）来控制C18：0水平的主要酶。 9）。SCD引起的C18：0蓄积强烈诱导VSMC中的严重脂毒性，导致血管平滑肌细胞的损伤。 钙化此外，我们的研究小组发现C18：0的促钙化作用是由两个主要的 通过与甘油-3-磷酸酰基转移酶-4（GPAT 4）的酶反应产生的C18：0的代谢物： 1)1，2-二硬脂酰磷脂酸（18：0/18：0-PA），通过激活 ER应激途径的PERK-eIF 2 β-ATF 4轴的表达和2）1-硬脂酰-溶血磷脂酸（18：0-LPA） 其通过形成异常MAM相关的omegasomes强烈抑制自噬通量， 这是自噬体形成的平台。C18：0通过激活 内质网应激反应和自噬抑制。然而，这种现象背后的分子机制 CKD介导的高磷酸盐血症转录抑制VSMC SCD的上游事件， 本文研究了我们相信，该机制的鉴定具有治疗潜力。去寻找 为了阐明这一机制，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质库。 基于表观遗传和转录化学文库筛选，我们鉴定了两个转录 抑制子候选者，有助于磷酸介导的SCD抑制和血管钙化。我们 因此，提出两个具体的目标，以阐明上游事件的调节脂毒性诱导 血管钙化目的1将研究是否转录阻遏物调节复合物影响 通过改变培养细胞中SCD的表达而引起的脂毒性和血管钙化。目标2将审查是否 转录阻遏物的调节影响体内磷酸毒性、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新的治疗靶点。