Tuesday, April 1, 2025
4/1/2025
The transcriptional control of vascular calcification in disease - 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.
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