Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, 651 Ilalo St. BSB222E, Honolulu, HI, USA.
Bio-Rad Laboratories, Inc., Hercules, CA, USA.
Sci Rep. 2021 Feb 16;11(1):3881. doi: 10.1038/s41598-021-82966-y.
ABCC6 deficiency promotes ectopic calcification; however, circumstantial evidence suggested that ABCC6 may also influence atherosclerosis. The present study addressed the role of ABCC6 in atherosclerosis using Ldlr mice and pseudoxanthoma elasticum (PXE) patients. Mice lacking the Abcc6 and Ldlr genes were fed an atherogenic diet for 16 weeks before intimal calcification, aortic plaque formation and lipoprotein profile were evaluated. Cholesterol efflux and the expression of several inflammation, atherosclerosis and cholesterol homeostasis-related genes were also determined in murine liver and bone marrow-derived macrophages. Furthermore, we examined plasma lipoproteins, vascular calcification, carotid intima-media thickness and atherosclerosis in a cohort of PXE patients with ABCC6 mutations and compared results to dysmetabolic subjects with increased cardiovascular risk. We found that ABCC6 deficiency causes changes in lipoproteins, with decreased HDL cholesterol in both mice and humans, and induces atherosclerosis. However, we found that the absence of ABCC6 does not influence overall vascular mineralization induced with atherosclerosis. Decreased cholesterol efflux from macrophage cells and other molecular changes such as increased pro-inflammation seen in both humans and mice are likely contributors for the phenotype. However, it is likely that other cellular and/or molecular mechanisms are involved. Our study showed a novel physiological role for ABCC6, influencing plasma lipoproteins and atherosclerosis in a haploinsufficient manner, with significant penetrance.
ABCC6 缺乏会促进异位钙化；然而，间接证据表明 ABCC6 也可能影响动脉粥样硬化。本研究使用 Ldlr 小鼠和假性黄色瘤弹性组织营养不良（PXE）患者来研究 ABCC6 在动脉粥样硬化中的作用。在给予致动脉粥样硬化饮食 16 周之前，缺失 Abcc6 和 Ldlr 基因的小鼠发生内膜钙化、主动脉斑块形成和脂蛋白谱进行了评估。还测定了小鼠肝脏和骨髓来源的巨噬细胞中的胆固醇外排以及几种炎症、动脉粥样硬化和胆固醇稳态相关基因的表达。此外，我们在携带 ABCC6 突变的 PXE 患者队列中检查了血浆脂蛋白、血管钙化、颈动脉内膜中层厚度和动脉粥样硬化，并将结果与心血管风险增加的代谢紊乱患者进行了比较。我们发现 ABCC6 缺乏会导致脂蛋白发生变化，无论是在小鼠还是在人类中，都会导致 HDL 胆固醇降低，并引发动脉粥样硬化。然而，我们发现 ABCC6 的缺失并不影响与动脉粥样硬化相关的整体血管矿化。从巨噬细胞中胆固醇外排减少以及在人和小鼠中都看到的其他分子变化，如炎症前体增加，可能是导致这种表型的原因。然而，可能涉及其他细胞和/或分子机制。我们的研究表明 ABCC6 具有新的生理作用，以半合子不足的方式影响血浆脂蛋白和动脉粥样硬化，具有显著的外显率。
