目的:糖尿病和高血压是血管疾病的重要危险因素,包括动脉粥样硬化.该过程中的驱动因素是脂质在血管壁的平滑肌细胞中的积累。葡萄糖和机械敏感性转录共激活因子,心肌素相关转录因子A(MRTF-A/MKL1)可以促进培养的人平滑肌细胞中的脂质积累,并有助于平滑肌源性泡沫细胞的形成。这项研究的目的是确定完整的人血管离体是否可用于评估血管壁中的脂质积累,并且如果该过程依赖于MRTF和/或半乳糖凝集素-3/LGALS3。半乳糖凝集素-3是平滑肌转分化的早期标志物,是泡沫细胞形成和动脉粥样硬化的潜在介质。
结果:在器官培养模型中,人类乳腺动脉和隐静脉暴露于改变的胆固醇和葡萄糖水平。脂质的积累,用油红O量化,胆固醇负荷和升高的葡萄糖浓度增加。CCG-203971对MRTF的药理学抑制减少了脂质积累,而腺病毒介导的MRTF-A过表达具有相反的作用。抑制MRTF后,胆固醇诱导的半乳糖凝集素3表达降低。重要的是,galectin-3与GB1107的药理学抑制减少了胆固醇负荷后血管壁中的脂质积累。
结论:人动脉和静脉的离体器官培养可用于评估完整血管壁中的脂质积累,以及腺病毒转导和药理抑制。虽然MRTF和半乳糖凝集素-3可能有益,在某些情况下的抗炎作用,我们的结果,这表明脂质积累显著减少,支持进一步评估MRTF和半乳糖凝集素-3抑制剂对动脉粥样硬化性血管疾病的治疗性干预。
OBJECTIVE: Diabetes and hypertension are important risk factors for vascular disease, including atherosclerosis. A driving factor in this process is lipid accumulation in smooth muscle cells of the vascular wall. The glucose- and mechano-sensitive transcriptional coactivator, myocardin-related transcription factor A (MRTF-A/MKL1) can promote lipid accumulation in cultured human smooth muscle cells and contribute to the formation of smooth muscle-derived foam cells. The purpose of this study was to determine if intact human blood vessels ex vivo can be used to evaluate lipid accumulation in the vascular wall, and if this process is dependent on MRTF and/or galectin-3/LGALS3. Galectin-3 is an early marker of smooth muscle transdifferentiation and a potential mediator for foam cell formation and atherosclerosis.
RESULTS: Human mammary arteries and saphenous veins were exposed to altered cholesterol and glucose levels in an organ culture model. Accumulation of lipids, quantified by Oil Red O, was increased by cholesterol loading and elevated glucose concentrations. Pharmacological inhibition of MRTF with CCG-203971 decreased lipid accumulation, whereas adenoviral-mediated overexpression of MRTF-A had the opposite effect. Cholesterol-induced expression of galectin-3 was decreased after inhibition of MRTF. Importantly, pharmacological inhibition of galectin-3 with GB1107 reduced lipid accumulation in the vascular wall after cholesterol loading.
CONCLUSIONS: Ex vivo organ culture of human arteries and veins can be used to evaluate lipid accumulation in the intact vascular wall, as well as adenoviral transduction and pharmacological inhibition. Although MRTF and galectin-3 may have beneficial, anti-inflammatory effects under certain circumstances, our results, which demonstrate a significant decrease in lipid accumulation, support further evaluation of MRTF- and galectin-3-inhibitors for therapeutic intervention against atherosclerotic vascular disease.