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A Microphysiological System to Study Leukocyte-Endothelial Cell Interaction during Inflammation
Published on: December 9, 2021
PHACTR1 regulates oxidative stress and inflammation to coronary artery endothelial cells via interaction with
Zhihui Zhang1, Fenglin Jiang1, Lixiong Zeng1
1Department of Cardiology, The Third Xiangya Hospital of Central South University, China.
Insights
Phosphatase and actin regulator 1 (PHACTR1) silencing reduces inflammation and oxidative stress in human coronary artery endothelial cells. PHACTR1 interacts with MRTF-A to promote NF-κB nuclear accumulation, a key pathway in atherosclerosis.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Atherosclerosis Research
Background:
- Genetic variants in PHACTR1 are linked to coronary artery disease and myocardial infarction.
- The precise role of PHACTR1 in the development of atherosclerosis is not yet understood.
Purpose of the Study:
- To elucidate the underlying mechanism of PHACTR1 in atherosclerosis.
- To investigate the role of PHACTR1 in regulating inflammation and oxidative stress in human coronary artery endothelial cells.
Main Methods:
- Assessed PHACTR1 and NF-κB signaling via immunoblots.
- Quantified reactive oxygen species (ROS) using flow cytometry.
- Determined PHACTR1-MRTF-A interaction using co-immunoprecipitation.
Main Results:
- PHACTR1 expression is elevated in human carotid plaques.
- PHACTR1 knockdown reduced inflammatory markers (ICAM-1, VCAM-1) and ROS levels.
- PHACTR1 silencing inhibited NF-κB p65 nuclear translocation by interacting with MRTF-A.
Conclusions:
- PHACTR1 promotes NF-κB nuclear accumulation and subsequent inflammation and oxidative stress in endothelial cells.
- Targeting PHACTR1 may offer a therapeutic strategy for atherosclerosis.
Background And Aims:
Genome-wide association studies have showed that genetic variants in phosphatase and actin regulator 1 (PHACTR1) are associated with coronary artery disease and myocardial infarction. However, the underlying mechanism of PHACTR1 in atherosclerosis remains unknown.
Methods:
Immunoblots were performed to evaluate the expression of PHACTR1 and phosphorylation of NF-κB signaling. Reactive oxygen species (ROS) labeled with DCFH-DA were assessed by flow cytometry. Fluorescence microscope was used to detect the translocation of p65 in human coronary artery endothelial cells (HACECs). Co-immunoprecipitation was performed to determine the interaction of PHACTR1 with MRTF-A.
Results:
The mRNA and protein levels of PHACTR1 were markedly increased in carotid plaquescompared with normal carotid arteries. Immunofluorescence staining indicated that PHACTR1 was constitutively expressed in endothelial cells in carotid plaques. Knockdown of PHACTR1 reduced excessive ICAM-1, VCAM-1 and VE-cadherin expression induced by oxidized low density lipoprotein (ox-LDL) in HCAECs. Additionally, silencing PHACTR1 alleviated p47phox phosphorylation and intracellular oxidative stress reflected by the reduction of ROS. Molecular experiments revealed that knockdown of PHACTR1 attenuated NF-κB activity without affecting IκBα and IKKα/β phosphorylation. In contrast, nuclear translation of p65 was blocked by depletion of PHACTR1. Furthermore, co-immunoprecipitation showed that PHACTR1 interacted with MRTF-A and p65 in HCAECs. Knockdown of MRTF-A suppressed the interaction of PHACTR1 with p65, subsequently blocking the nuclear translocation of p65.
Conclusions:
Our finding suggest that silencing PHACTR1 alleviates the nuclear accumulation of p65 and NF-κB via interaction with MRTF-A, ensuing attenuating oxidative stress and inflammation in HCAECs.
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