MED1 Deficiency in Macrophages Accelerates Intimal Hyperplasia via ROS Generation and Inflammation

Abstract

Mediator complex subunit 1 (MED1) is a component of the mediator complex and functions as a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Previously, we showed that MED1 in macrophages has a protective effect on atherosclerosis; however, the effect of MED1 on intimal hyperplasia and mechanisms regulating proinflammatory cytokine production after macrophage MED1 deletion are still unknown. In this study, we report that MED1 macrophage-specific knockout (MED1ΔMac) mice showed aggravated neointimal hyperplasia, vascular smooth muscle cells (VSMCs), and macrophage accumulation in injured arteries. Moreover, MED1ΔMac mice showed increased proinflammatory cytokine production after an injury to the artery. After lipopolysaccharide (LPS) treatment, MED1ΔMac macrophages showed increased generation of reactive oxygen species (ROS) and reduced expression of peroxisome proliferative activated receptor gamma coactivator-1α (PGC1α) and antioxidant enzymes, including catalase and glutathione reductase. The overexpression of PGC1α attenuated the effects of MED1 deficiency in macrophages. In vitro, conditioned media from MED1ΔMac macrophages induced more proliferation and migration of VSMCs. To explore the potential mechanisms by which MED1 affects inflammation, macrophages were treated with BAY11-7082 before LPS treatment, and the results showed that MED1ΔMac macrophages exhibited increased expression of phosphorylated-p65 and phosphorylated signal transducer and activator of transcription 1 (p-STAT1) compared with the control macrophages, suggesting the enhanced activation of NF-κB and STAT1. In summary, these data showed that MED1 deficiency enhanced inflammation and the proliferation and migration of VSMCs in injured vascular tissue, which may result from the activation of NF-κB and STAT1 due to the accumulation of ROS.

Myricanol Inhibits Platelet Derived Growth Factor-BB-Induced Vascular Smooth Muscle Cells Proliferation and Migration in vitro and Intimal Hyperplasia in vivo by Targeting the Platelet-Derived Growth Factor Receptor-β and NF-κB Signaling

“…Therefore, we assessed the effect of myricanol on intimal hyperplasia after carotid artery wire ligation and found that 14-day' treatment of myricanol can significantly diminish the intimal hyperplasia. In addition, inflammatory cytokines produced by activated macrophages are the direct promoters of neointimal formation (Zhang et al, 2021). And our results showed that myricanol can also inhibit the macrophage infiltration after carotid artery wire ligation.…”

“…Immunofluorescence staining showed that the myricanol-treated ligation surgery group had significantly inhibited Ki67 expression (Supplementary Figures 5A,B). In addition, macrophages are known to play a role in the progression of intimal hyperplasia and other cardiovascular disorders (Zhang et al, 2021). Our results exhibited that the expression of F4/80 significantly increased in the ligation surgery group comparing with the sham surgery group, While the myricanol treatement significantly decreased F4/80 expression (Supplementary Figures 5C,D).…”

Transcriptional and Epigenetic Factors Associated with Early Thrombosis of Femoral Artery Involved in Arteriovenous Fistula

“…Activated ARNT2 in this study might be a therapeutic target to facilitate AVF maturation, as aryl hydrocarbons have been suggested as a therapeutic target in cardiovascular diseases [ 28 , 29 ]. Excessive intimal hyperplasia is also a result of increased ROS production and inflammation, mediated by macrophages that are deficient in MED1 [ 30 ]. Inhibited MED1 ( Table 6 ) and the infiltration of pro-inflammatory immune cells, including macrophages, in the thrombosed and intimal hyperplasia region of femoral arteries in this study support the notion of the presence of inflammation [ 12 ] and a the possible role of MED1-deficient macrophages in early thrombosis and AVF failure.…”

Interleukin 6-regulated macrophage polarization controls atherosclerosis-associated vascular intimal hyperplasia

“…Vascular Intimal hyperplasia (VIH) is a process in which the vascular intima becomes thickened due to the appearance of unexpected cells and proteoglycan-rich extracellular matrix between the internal elastic lamina of the vessels and vascular endothelia ( 3 ). It has been found that VIH increases lipoprotein retention in the vascular intima and accelerated atherosclerosis, and thus becomes an initial pathological process for AS development ( 4 ).…”

“…VIH contains cell types including macrophages that could transform into foam cells, which are critical for plaque formation ( 7 ). It is known that plaque macrophages are heterogeneous ( 4 ). Recently, it was shown that CD11c+ macrophages appeared to be more involved in active plaque progression ( 8 ).…”