Shearston Kate, Tan Joanne T M, Cochran Blake J, Rye Kerry-Anne
Lipid Research Group, Faculty of Medicine, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
Vascular Research Centre, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia.
Front Cardiovasc Med. 2022 Jun 30;9:901408. doi: 10.3389/fcvm.2022.901408. eCollection 2022.
Apolipoprotein (apo) A-IV, the third most abundant apolipoprotein in human high density lipoproteins (HDLs), inhibits intestinal and systemic inflammation. This study asks if apoA-IV also inhibits acute vascular inflammation.
Inflammation was induced in New Zealand White rabbits by placing a non-occlusive silastic collar around the common carotid artery. A single 1 mg/kg intravenous infusion of lipid-free apoA-IV or saline (control) was administered to the animals 24 h before collar insertion. The animals were euthanised 24 h post-collar insertion. Human coronary artery cells (HCAECs) were pre-incubated with reconstituted HDLs containing apoA-IV complexed with phosphatidylcholine, (A-IV)rHDLs, then activated by incubation with tumour necrosis factor (TNF)-α. Cell surface vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) in the TNF-α-activated HCAECs was quantified by flow cytometry. VCAM-1, ICAM-1 and 3β-hydroxysteroid-Δ24 reductase (DHCR24) mRNA levels were quantified by real time PCR.
Apolipoprotein ApoA-IV treatment significantly decreased collar-induced endothelial expression of VCAM-1, ICAM-1 and neutrophil infiltration into the arterial intima by 67.6 ± 9.9% ( < 0.01), 75.4 ± 6.9% ( < 0.01) and 74.4 ± 8.5% ( < 0.05), respectively. It also increased endothelial expression of DHCR24 by 2.6-fold ( < 0.05). Pre-incubation of HCAECs with (A-IV)rHDLs prior to stimulation with TNF-α inhibited VCAM-1 and ICAM-1 protein levels by 62.2 ± 12.1% and 33.7 ± 5.7%, respectively. VCAM-1 and ICAM-1 mRNA levels were decreased by 55.8 ± 7.2% and 49.6 ± 7.9%, respectively, while DHCR24 mRNA expression increased by threefold. Transfection of HCAECs with DHCR24 siRNA attenuated the anti-inflammatory effects of (A-IV)rHDLs. Pre-incubation of TNF-α-activated HCAECs with (A-IV)rHDLs also inhibited nuclear translocation of the p65 subunit of nuclear factor-κB (NF-κB), and decreased IκBα phosphorylation.
These results indicate that apoA-IV inhibits vascular inflammation and by inhibiting NF-κB activation in a DHCR24-dependent manner.
载脂蛋白（apo）A-IV是人类高密度脂蛋白（HDL）中含量第三丰富的载脂蛋白，可抑制肠道和全身炎症。本研究探讨apoA-IV是否也能抑制急性血管炎症。
通过在新西兰白兔的颈总动脉周围放置一个非阻塞性硅橡胶套环来诱导炎症。在套环插入前24小时，给动物静脉注射单次1mg/kg无脂apoA-IV或生理盐水（对照）。套环插入后24小时对动物实施安乐死。将人冠状动脉内皮细胞（HCAECs）与含有与磷脂酰胆碱复合的apoA-IV的重组HDL（A-IV）rHDLs预孵育，然后用肿瘤坏死因子（TNF）-α孵育激活。通过流式细胞术对TNF-α激活的HCAECs中的细胞表面血管细胞黏附分子-1（VCAM-1）和细胞间黏附分子-1（ICAM-1）进行定量。通过实时PCR对VCAM-1、ICAM-1和3β-羟基类固醇-Δ24还原酶（DHCR24）的mRNA水平进行定量。
载脂蛋白ApoA-IV治疗显著降低了套环诱导的VCAM-1、ICAM-1的内皮表达以及中性粒细胞向动脉内膜的浸润，分别降低了67.6±9.9%（P<0.01）、75.4±6.9%（P<0.01）和74.4±8.5%（P<0.05）。它还使DHCR24的内皮表达增加了2.6倍（P<0.05）。在TNF-α刺激之前，用（A-IV）rHDLs对HCAECs进行预孵育，可使VCAM-1和ICAM-1蛋白水平分别降低62.2±12.1%和33.7±5.7%。VCAM-1和ICAM-1的mRNA水平分别降低了
