Atherosclerosis ( IF 4.9 ) Pub Date : 2021-07-01 , DOI: 10.1016/j.atherosclerosis.2021.06.927 Cassidy M R Blackburn 1 , Robert M Schilke 1 , Aimee E Vozenilek 1 , Sunitha Chandran 1 , Temitayo T Bamgbose 1 , Brian N Finck 2 , Matthew D Woolard 1
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Background and aims
Atherosclerosis is the most prominent underlying cause of cardiovascular disease (CVD). It is initiated by cholesterol deposition in the arterial intima, which causes macrophage recruitment and proinflammatory responses that promote plaque growth, necrotic core formation, and plaque rupture. Lipin-1 is a phosphatidic acid phosphohydrolase for glycerolipid synthesis. We have shown that lipin-1 phosphatase activity promotes macrophage pro-inflammatory responses when stimulated with modified low-density lipoprotein (modLDL) and accelerates atherosclerosis. Lipin-1 also independently acts as a transcriptional co-regulator where it enhances the expression of genes involved in β-oxidation. In hepatocytes and adipocytes, lipin-1 augments the activity of transcription factors such as peroxisome proliferator-activated receptor (PPARs). PPARs control the expression of anti-inflammatory genes in macrophages and slow or reduce atherosclerotic progression. Therefore, we hypothesize myeloid-derived lipin-1 transcriptional co-regulatory activity reduces atherosclerosis.
Methods
We used myeloid-derived lipin-1 knockout (lipin-1mKO) and littermate control mice and AAV8-PCSK9 along with high-fat diet to elicit atherosclerosis.
Results
Lipin-1mKO mice had larger aortic root plaques than littermate control mice after 8 and 12 weeks of a high-fat diet. Lipin-1mKO mice also had increased serum proinflammatory cytokine concentrations, reduced apoptosis in plaques, and larger necrotic cores in the plaques compared to control mice.
Conclusions
Combined, the data suggest lipin-1 transcriptional co-regulatory activity in myeloid cells is atheroprotective.
中文翻译：
骨髓相关的 lipin-1 转录共调节活性具有动脉粥样硬化保护作用
背景和目标
动脉粥样硬化是心血管疾病（CVD）最突出的根本原因。它由动脉内膜中的胆固醇沉积引发，这会引起巨噬细胞募集和促炎反应，从而促进斑块生长、坏死核心形成和斑块破裂。Lipin-1 是一种用于甘油脂合成的磷脂酸磷酸水解酶。我们已经表明，当用修饰的低密度脂蛋白 (modLDL) 刺激时，lipin-1 磷酸酶活性会促进巨噬细胞的促炎反应并加速动脉粥样硬化。Lipin-1 还独立地充当转录共调节剂，它增强参与 β 氧化的基因的表达。在肝细胞和脂肪细胞中，lipin-1 增强了转录因子的活性，例如过氧化物酶体增殖物激活受体 (PPAR)。PPARs 控制巨噬细胞中抗炎基因的表达，减缓或减少动脉粥样硬化的进展。因此，我们假设骨髓来源的 lipin-1 转录共调节活性可减少动脉粥样硬化。
方法
我们使用骨髓来源的 lipin-1 敲除 ( lipin-1mKO ) 和同窝对照小鼠以及 AAV8-PCSK9 以及高脂肪饮食来诱发动脉粥样硬化。
结果
在高脂饮食 8 周和 12 周后，Lipin-1mKO小鼠的主动脉根斑块比同窝对照小鼠大。与对照小鼠相比， Lipin-1mKO小鼠的血清促炎细胞因子浓度也增加，斑块中的细胞凋亡减少，并且斑块中的坏死核心更大。
结论
结合起来，数据表明骨髓细胞中的 lipin-1 转录共调节活性具有动脉粥样硬化保护作用。
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