Department of Cardiology, Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People's Republic of China.
Department of Cardiology, Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People's Republic of China.
J Mol Cell Cardiol. 2018 Mar;116:69-80. doi: 10.1016/j.yjmcc.2018.01.013. Epub 2018 Feb 3.
Human genome-wide association studies (GWAS) have found that proline/serine-rich coiled-coil 1 (PSRC1) encodes a protein that is associated with serum lipid levels and coronary artery disease. In addition, our previous study showed that the cholesterol efflux capacity is decreased in macrophages following a treatment silencing Psrc1, indicating that PSRC1 has anti-atherosclerotic effects. However, the role of PSRC1 in the development of atherosclerosis is unknown. This study aims to explore the effect of PSRC1 on atherosclerosis and its underlying mechanisms.
A recombinant adenovirus expressing Psrc1 (Ad-PSRC1) was constructed and transfected in RAW264.7 cells as well as injected intravenously into apoE mice. The in vitro study showed that PSRC1 overexpression reduced the cellular cholesterol content, increased the cholesterol efflux capacity and inhibited foam cell formation by upregulating the expression of peroxisome proliferator-activated receptor γ (PPAR-γ) and liver X receptor α (LXR-α), which are key cholesterol transportation-related proteins. Infecting apoE mice with Ad-PSRC1 inhibited the development of atherosclerotic lesions and enhanced atherosclerotic plaque stability. Consistent with these results, PSRC1 overexpression in apoE mice decreased the plasma levels of TC, TG, LDL-C, TNF-α, IL-1β and IL-6, increased the plasma HDL-C levels and improved HDL function. Similarly, the PPAR-γ and LXR-α expression levels were upregulated in the liver and in peritoneal macrophages of PSRC1-overexpressing apoE mice. Finally, the liver and peritoneal macrophages of apoE mice displayed elevated expression of β-catenin, which is a direct downstream gene of PSRC1 and an upstream gene of PPAR-γ and LXR-α, but decreased activity of nuclear transcription factor (NF-κB), which acts as a key gene in the regulation of inflammation.
PSRC1 protects against the development of atherosclerosis and enhances the stability of plaques by modulating cholesterol transportation and inflammation in macrophages and the liver of apoE mice.
人类全基因组关联研究（GWAS）发现脯氨酸/丝氨酸丰富卷曲螺旋 1（PSRC1）编码的蛋白与血清脂质水平和冠状动脉疾病有关。此外，我们之前的研究表明，沉默 Psrc1 后巨噬细胞中的胆固醇流出能力降低，表明 PSRC1 具有抗动脉粥样硬化作用。然而，PSRC1 在动脉粥样硬化发展中的作用尚不清楚。本研究旨在探讨 PSRC1 对动脉粥样硬化的影响及其潜在机制。
构建了表达 Psrc1 的重组腺病毒（Ad-PSRC1），并转染 RAW264.7 细胞，以及静脉注射到载脂蛋白 E（apoE）小鼠体内。体外研究表明，PSRC1 过表达通过上调过氧化物酶体增殖物激活受体γ（PPAR-γ）和肝 X 受体α（LXR-α）的表达，降低细胞内胆固醇含量，增加胆固醇流出能力，抑制泡沫细胞形成，这些蛋白是关键的胆固醇转运相关蛋白。用 Ad-PSRC1 感染 apoE 小鼠可抑制动脉粥样硬化病变的发展，并增强动脉粥样硬化斑块的稳定性。与这些结果一致，apoE 小鼠中 PSRC1 的过表达降低了 TC、TG、LDL-C、TNF-α、IL-1β 和 IL-6 的血浆水平，增加了 HDL-C 的血浆水平并改善了 HDL 功能。同样，PSRC1 过表达apoE 小鼠的肝脏和腹腔巨噬细胞中 PPAR-γ 和 LXR-α 的表达水平上调。最后，apoE 小鼠的肝脏和腹腔巨噬细胞中β-连环蛋白的表达升高，β-连环蛋白是 PSRC1 的直接下游基因，也是 PPAR-γ 和 LXR-α 的上游基因，而核转录因子（NF-κB）的活性降低，NF-κB 是调节炎症的关键基因。
PSRC1 通过调节 apoE 小鼠巨噬细胞和肝脏中的胆固醇转运和炎症，防止动脉粥样硬化的发展并增强斑块的稳定性。
