PAK1 Silencing Attenuated Proinflammatory Macrophage Activation and Foam Cell Formation by Increasing PPARγ Expression

Abstract

Macrophage polarization in response to environmental cues has emerged as an important event in the development of atherosclerosis. Compelling evidences suggest that P21-activated kinases 1 (PAK1) is involved in a wide variety of diseases. However, the potential role and mechanism of PAK1 in regulation of macrophage polarization remains to be elucidated. Here, we observed that PAK1 showed a dramatically increased expression in M1 macrophages but decreased expression in M2 macrophages by using a well-established in vitro model to study heterogeneity of macrophage polarization. Adenovirus-mediated loss-of-function approach demonstrated that PAK1 silencing induced an M2 macrophage phenotype-associated gene profiles but repressed the phenotypic markers related to M1 macrophage polarization. Additionally, dramatically decreased foam cell formation was found in PAK1 silencing-induced M2 macrophage activation which was accompanied with alternation of marker account for cholesterol efflux or influx from macrophage foam cells. Moderate results in lipid metabolism and foam cell formation were found in M1 macrophage activation mediated by AdshPAK1. Importantly, we presented mechanistic evidence that PAK1 knockdown promoted the expression of PPARγ, and the effect of macrophage activation regulated by PAK1 silencing was largely reversed when a PPARγ antagonist was utilized. Collectively, these findings reveal that PAK1 is an independent effector of macrophage polarization at least partially attributed to regulation of PPARγ expression, which suggested PAK1-PPARγ axis as a novel therapeutic strategy in atherosclerosis management.

The P21-Activated Kinase 1 and 2 As Potential Therapeutic Targets for the Management of Cardiovascular Disease

“…Macrophages play key roles in inflammation during the development of atherosclerosis. Pak1 expression was reported to upregulate in M1 macrophages but downregulate in M2 macrophages in isolated bone marrow-derived macrophages and peritoneal macrophages of ApoE -/mice [57]. It was also reported that Pak1 knockdown led to increase the anti-inflammatory M2 macrophages activation markers expression (IL-10, arginase-1) and decrease the pro-inflammatory M1 macrophages activation markers expression (IL-6, IL-1β) [57].…”

Lactobacillus johnsonii YH1136 plays a protective role against endogenous pathogenic bacteria induced intestinal dysfunction by reconstructing gut microbiota in mice exposed at high altitude

“…In addition to the miR-196a-1-3p and miR-3060-3p, miR-485-5p, miR-7219-3p, and miR-103-2-5p were also of interest, and their target gene were predicted using the miRDB database. After screening, we found that a target gene of miR-485-5p, Pak1, the p21 activated kinase, is associated with multiple diseases ( 64 , 65 ) and may play a regulatory role in intestinal inflammation induced by a high-altitude hypoxic environment. Overexpression studies of PAK1, which has been shown to have higher expression in inflammatory bowel disease, showed higher cell proliferation and reduced apoptosis when overexpressed ( 66 ).…”

Role of Inflammation, Oxidative Stress, and Mitochondrial Changes in Premenstrual Psychosomatic Behavioral Symptoms with Anti-Inflammatory, Antioxidant Herbs, and Nutritional Supplements

“…A prevalence study on PMS women reported a correlation between inflammatory factors elevated levels (IL-2, IL-4, IL-10, and IL-12) and the total symptom score in PMS, and further, higher correlations were noted for IL-12, IL-10, and PMS symptoms [ 14 ]. P21-activated kinase 1 (PAK1) plays a critical role and contributes to various diseases including inflammation, immunosuppression, cancer, viral infection, ageing, and diabetes [ 77 ]. Zeinolabediny et al [ 78 ] discussed the inflammatory disease associated with cardiovascular complications.…”