University of Maryland, Department of Nutrition and Food Science, College Park, MD 20742, USA.
University of Maryland, The Fischell Department of Bioengineering, College Park, MD 20742, USA.
Free Radic Biol Med. 2017 Sep;110:142-150. doi: 10.1016/j.freeradbiomed.2017.06.004. Epub 2017 Jun 8.
Cardiovascular disease is the number one cause of death in United States, and atherosclerosis, a chronic inflammatory arterial disease, is the most dominant underlying pathology. Macrophages are thought to orchestrate atherosclerosis by generating lipid-laden foam cells and by secreting inflammatory mediators. Emerging data support a role for a mechanical factor, e.g., matrix stiffness, in regulation of macrophage function, vascular elasticity, and atherogenesis. However, the identity of the plasma membrane mechanosensor and the mechanisms by which pro-atherogenic signals are transduced/maintained are unknown. We have obtained evidence that TRPV4, an ion channel in the transient receptor potential vanilloid family and a known mechanosensor, is the likely mediator of oxidized low-density lipoprotein (oxLDL)-dependent macrophage foam cell formation, a critical process in atherogenesis. Specifically, we found that: i) genetic ablation of TRPV4 or pharmacologic inhibition of TRPV4 activity by a specific antagonist blocked oxLDL-induced macrophage foam cell formation, and ii) TRPV4 deficiency prevented pathophysiological range matrix stiffness or scratch-induced exacerbation of oxLDL-induced foam cell formation. Mechanistically, we found that: i) plasma membrane localization of TRPV4 was sensitized to the increasing level of matrix stiffness, ii) lack of foam cell formation in TRPV4 null cells was not due to lack of expression of CD36, a major receptor for oxLDL, and iii) TRPV4 channel activity regulated oxLDL uptake but not its binding on macrophages. Altogether, these findings identify a novel role for TRPV4 in regulating macrophage foam cell formation by modulating uptake of oxLDL. These findings suggest that therapeutic targeting of TRPV4 may provide a selective approach to the treatment of atherosclerosis.
心血管疾病是美国头号死因，动脉粥样硬化是最主要的潜在病理学，是一种慢性炎症性动脉疾病。巨噬细胞被认为通过产生富含脂质的泡沫细胞和分泌炎症介质来调节动脉粥样硬化。新出现的数据支持机械因素（例如基质硬度）在调节巨噬细胞功能、血管弹性和动脉粥样硬化形成中的作用。然而，尚不清楚质膜机械感受器的身份以及前动脉粥样硬化信号转导/维持的机制。我们已经获得了证据，证明瞬时受体电位香草素家族中的离子通道 TRPV4 是一种已知的机械感受器，可能是氧化低密度脂蛋白 (oxLDL) 依赖性巨噬细胞泡沫细胞形成的介体，这是动脉粥样硬化形成的关键过程。具体而言，我们发现：i）TRPV4 的基因缺失或特定拮抗剂对 TRPV4 活性的药理抑制阻断了 oxLDL 诱导的巨噬细胞泡沫细胞形成，ii）TRPV4 缺乏可防止生理范围的基质硬度或划痕诱导的 oxLDL 诱导的泡沫细胞形成加剧。从机制上讲，我们发现：i）TRPV4 的质膜定位对基质硬度的增加变得敏感，ii）TRPV4 缺失细胞中缺乏泡沫细胞形成不是由于 oxLDL 的主要受体 CD36 表达缺失，iii）TRPV4 通道活性调节 oxLDL 的摄取，但不调节 oxLDL 在巨噬细胞上的结合。总而言之，这些发现确定了 TRPV4 在调节巨噬细胞泡沫细胞形成中的新作用，通过调节 oxLDL 的摄取来调节巨噬细胞泡沫细胞形成。这些发现表明，针对 TRPV4 的治疗靶向可能为动脉粥样硬化的治疗提供一种选择性方法。
