Cell Regeneration Research Center, Chonnam National University Hospital, Gwangju, South Korea.
Department of Cardiology, Chonnam National University Medical School, Gwangju, Republic of Korea.
Exp Mol Med. 2023 Feb;55(2):426-442. doi: 10.1038/s12276-023-00937-x. Epub 2023 Feb 13.
Atherosclerosis, the leading cause of death, is a vascular disease of chronic inflammation. We recently showed that angiopoietin-like 4 (ANGPTL4) promotes cardiac repair by suppressing pathological inflammation. Given the fundamental contribution of inflammation to atherosclerosis, we assessed the role of ANGPTL4 in the development of atherosclerosis and determined whether ANGPTL4 regulates atherosclerotic plaque stability. We injected ANGPTL4 protein twice a week into atherosclerotic Apoe-/- mice and analyzed the atherosclerotic lesion size, inflammation, and plaque stability. In atherosclerotic mice, ANGPTL4 reduced atherosclerotic plaque size and vascular inflammation. In the atherosclerotic lesions and fibrous caps, the number of α-SMA(+), SM22α(+), and SM-MHC(+) cells was higher, while the number of CD68(+) and Mac2(+) cells was lower in the ANGPTL4 group. Most importantly, the fibrous cap was significantly thicker in the ANGPTL4 group than in the control group. Smooth muscle cells (SMCs) isolated from atherosclerotic aortas showed significantly increased expression of CD68 and Krüppel-like factor 4 (KLF4), a modulator of the vascular SMC phenotype, along with downregulation of α-SMA, and these changes were attenuated by ANGPTL4 treatment. Furthermore, ANGPTL4 reduced TNFα-induced NADPH oxidase 1 (NOX1), a major source of reactive oxygen species, resulting in the attenuation of KLF4-mediated SMC phenotypic changes. We showed that acute myocardial infarction (AMI) patients with higher levels of ANGPTL4 had fewer vascular events than AMI patients with lower levels of ANGPTL4 (p < 0.05). Our results reveal that ANGPTL4 treatment inhibits atherogenesis and suggest that targeting vascular stability and inflammation may serve as a novel therapeutic strategy to prevent and treat atherosclerosis. Even more importantly, ANGPTL4 treatment inhibited the phenotypic changes of SMCs into macrophage-like cells by downregulating NOX1 activation of KLF4, leading to the formation of more stable plaques.
动脉粥样硬化是导致死亡的主要原因，是一种慢性炎症性血管疾病。我们最近发现，血管生成素样蛋白 4（ANGPTL4）通过抑制病理性炎症促进心脏修复。鉴于炎症对动脉粥样硬化的基本贡献，我们评估了 ANGPTL4 在动脉粥样硬化发展中的作用，并确定 ANGPTL4 是否调节动脉粥样硬化斑块的稳定性。我们每周两次向动脉粥样硬化 Apoe-/-小鼠注射 ANGPTL4 蛋白，并分析动脉粥样硬化病变大小、炎症和斑块稳定性。在动脉粥样硬化小鼠中，ANGPTL4 降低了动脉粥样硬化斑块的大小和血管炎症。在动脉粥样硬化病变和纤维帽中，ANGPTL4 组的 α-SMA(+)、SM22α(+)和 SM-MHC(+)细胞数量较高，而 CD68(+)和 Mac2(+)细胞数量较低。最重要的是，ANGPTL4 组的纤维帽明显比对照组厚。从动脉粥样硬化主动脉中分离的平滑肌细胞（SMCs）显示出明显增加的 CD68 和 Krüppel 样因子 4（KLF4）表达，KLF4 是血管 SMC 表型的调节剂，同时下调 α-SMA，这些变化被 ANGPTL4 治疗减弱。此外，ANGPTL4 减少了肿瘤坏死因子 α（TNFα）诱导的 NADPH 氧化酶 1（NOX1），NOX1 是活性氧的主要来源，导致 KLF4 介导的 SMC 表型变化减弱。我们发现，ANGPTL4 水平较高的急性心肌梗死（AMI）患者的血管事件少于 ANGPTL4 水平较低的 AMI 患者（p<0.05）。我们的结果表明，ANGPTL4 治疗抑制动脉粥样硬化形成，并表明靶向血管稳定性和炎症可能是预防和治疗动脉粥样硬化的新治疗策略。更重要的是，ANGPTL4 治疗通过下调 NOX1 对 KLF4 的激活抑制 SMC 向巨噬细胞样细胞的表型变化，导致形成更稳定的斑块。
