Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, LA, United States.
Division of Geriatrics and Nutritional Science, Washington University School of Medicine, St. Louis, MO, United States.
Atherosclerosis. 2021 Aug;330:76-84. doi: 10.1016/j.atherosclerosis.2021.06.927. Epub 2021 Jul 1.
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.
We used myeloid-derived lipin-1 knockout (lipin-1mKO) and littermate control mice and AAV8-PCSK9 along with high-fat diet to elicit atherosclerosis.
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.
Combined, the data suggest lipin-1 transcriptional co-regulatory activity in myeloid cells is atheroprotective.
动脉粥样硬化是心血管疾病（CVD）最突出的潜在病因。它是由胆固醇在动脉内膜中的沉积引起的，导致巨噬细胞募集和促炎反应，促进斑块生长、坏死核心形成和斑块破裂。脂磷肌醇-1 是甘油磷脂合成的磷酸脂酶。我们已经表明，脂磷肌醇-1 磷酸酶活性在受到修饰的低密度脂蛋白（modLDL）刺激时促进巨噬细胞的促炎反应，并加速动脉粥样硬化。脂磷肌醇-1 还可以作为转录共调节剂独立发挥作用，增强涉及β-氧化的基因的表达。在肝细胞和脂肪细胞中，脂磷肌醇-1 增强转录因子如过氧化物酶体增殖物激活受体（PPARs）的活性。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，我们假设髓样细胞来源的脂磷肌醇-1 转录共调节活性可减少动脉粥样硬化。
我们使用髓样细胞来源的脂磷肌醇-1 敲除（lipin-1mKO）和同窝对照小鼠以及 AAV8-PCSK9 联合高脂肪饮食来引发动脉粥样硬化。
高脂饮食 8 周和 12 周后，lipin-1mKO 小鼠的主动脉根部斑块比同窝对照小鼠大。lipin-1mKO 小鼠的血清促炎细胞因子浓度升高，斑块中的细胞凋亡减少，斑块中的坏死核心更大。
综合数据表明，髓样细胞中的脂磷肌醇-1 转录共调节活性具有抗动脉粥样硬化作用。
