bims-noxint Biomed News
on NADPH oxidases in tumorigenesis
Issue of 2021‒03‒21
five papers selected by
Laia Caja Puigsubira
Uppsala University

  1. Free Radic Biol Med. 2021 Mar 16. pii: S0891-5849(21)00113-1. [Epub ahead of print]
      Chemokines have been reported to play important roles in atherosclerotic development. Recently, we found C-C motif ligand 8 (CCL8), a rarely studied chemokine in atherosclerosis, was highly expressed in the endothelium of advanced human carotid plaques. We hypothesized whether CCL8 promotes atherosclerosis through endothelial dysfunction. Apolipoprotein E-deficient mice under the Western diet were used to construct atherosclerosis models. Adeno-associated viruses (AAV) with CCL8 and the CCL8-antibody were injected into mice respectively to conduct CCL8 overexpression and suppression. The results showed that atherosclerotic lesions were significantly increased in the AAV-CCL8 group, while, lesions in the aortic sinus were reduced in the CCL8-antibody group. With CCL8 treatment (200ng/ml, 24h) in vitro, the permeability of human aortic endothelial cells (HAECs) increased and the expression of junctional proteins Zonula occluden-1, and Vascular endothelial cadherin were decreased. This effect was dependent on reactive oxygen species (ROS) generation, which could be blocked by L-Ascorbic acid and Apocynin. Results showed that NADPH oxidase 2 (NOX2) expression also increased with CCL8 stimulation and the ROS, and permeability increase of HAECs could be inhibited when NOX2 interfered with the specific siRNA. Additionally, we further found ERK1/2, PI3K-AKT, and NF-κB pathways were involved in the activation of CCL8. Our results indicated that CCL8 might also play important roles in atherosclerosis and this effect, at least in part, was caused by NOX2/ROS-induced endothelial permeability increase. This study might contribute to a deeper understanding of the connection between chemokines and atherosclerosis.
    Keywords:  Atherosclerosis; C-C motif ligand 8; Endothelial permeability; Reactive oxygen species
  2. Free Radic Biol Med. 2021 Mar 15. pii: S0891-5849(21)00159-3. [Epub ahead of print]
      NADPH oxidase (Nox) mediates ROS production and contributes to cardiac remodeling. However, macrophage p47phox, a Nox subunit regulating cardiac remodeling, is unclear. We aimed to investigate the role of macrophage p47phox in hypertensive cardiac remodeling. Pressure-overload induced by Angiotensin II (AngII) for two weeks in young adult male p47phox deficient (KO) mice showed aggravated cardiac dysfunction and hypertrophy as indicated from echocardiographic and histological studies in comparison with wild-type littermates (WT). Additionally, LV of AngII-infused KO mice showed augmented interstitial fibrosis, collagen deposition and, myofibroblasts compared to AngII-infused WT mice. Moreover, these changes in AngII-infused KO mice correlated well with the gene analysis of hypertrophic and fibrotic markers. Similar results were also found in the transverse aortic constriction model. Further, AngII-infused KO mice showed elevated circulating immunokines and increased LV leukocytes infiltration and CD206+ macrophages compared to AngII-infused WT mice. Likewise, LV of AngII-infused KO mice showed upregulated mRNA expression of anti-inflammatory/pro-fibrotic M2 macrophage markers (Ym1, Arg-1) compared to AngII-infused WT mice. AngII and IL-4 treated bone marrow-derived macrophages (BMDMs) from KO mice showed upregulated M2 macrophage markers and STAT6 phosphorylation (Y641) compared to AngII and IL-4 treated WT BMDMs. These alterations were at least partly mediated by macrophage as bone marrow transplantation from KO mice into WT mice aggravated cardiac remodelling. Mechanistically, AngII-infused KO mice showed hyperactivated IL-4/STAT6/PPARγ signaling and downregulated SOCS3 expression compared to AngII-infused WT mice. Our studies show that macrophage p47phox limits anti-inflammatory signaling and extracellular matrix remodeling in response to pressure-overload.
    Keywords:  Angiotensin II; fibrosis; hypertension; hypertrophy; macrophages; p47(phox)
  3. Cell Commun Signal. 2021 Mar 18. 19(1): 35
      BACKGROUND: The mechanism underlying endothelial dysfunction leading to cardiovascular disease in type 2 diabetes mellitus (T2DM) remains unclear. Here, we show that inhibition of histone deacetylase 3 (HDAC3) reduced inflammation and oxidative stress by regulating nuclear factor-E2-related factor 2 (Nrf2), which mediates the expression of anti-inflammatory- and pro-survival-related genes in the vascular endothelium, thereby improving endothelial function.METHODS: Nrf2 knockout (Nrf2 KO) C57BL/6 background mice, diabetic db/db mice, and control db/m mice were used to investigate the relationship between HDAC3 and Nrf2 in the endothelium in vivo. Human umbilical vein endothelial cells (HUVECs) cultured under high glucose-palmitic acid (HG-PA) conditions were used to explore the role of Kelch-like ECH-associated protein 1 (Keap1) -Nrf2-NAPDH oxidase 4 (Nox4) redox signaling in the vascular endothelium in vitro. Activity assays, immunofluorescence, western blotting, qRT-PCR, and immunoprecipitation assays were used to examine the effect of HDAC3 inhibition on inflammation, reactive oxygen species (ROS) production, and endothelial impairment, as well as the activity of Nrf2-related molecules.
    RESULTS: HDAC3 activity, but not its expression, was increased in db/db mice. This resulted in de-endothelialization and increased oxidative stress and pro-inflammatory marker expression in cells treated with the HDAC3 inhibitor RGFP966, which activated Nrf2 signaling. HDAC3 silencing decreased ROS production, inflammation, and damage-associated tube formation in HG-PA-treated HUVECs. The underlying mechanism involved the Keap1-Nrf2-Nox4 signaling pathway.
    CONCLUSION: The results of this study suggest the potential of HDAC3 as a therapeutic target for the treatment of endothelial dysfunction in T2DM. Video Abstract.
    Keywords:  Endothelial dysfunction; HDAC3; Nrf2; T2DM
  4. Cell Mol Neurobiol. 2021 Mar 19.
      Glioblastoma multiforme (GBM) is account for 70% of all primary malignancies of the central nervous system. The median survival of human patients after treatment is around 15 months. There are several biological targets which have been reported that can be pursued using ligands with varied structures to treat this disease. In our group, we have developed several ligands that target a wide range of proteins involved in anticancer effects, such as histone deacetylase (HDACs), G protein-coupled estrogen receptor 1 (GPER), estrogen receptor-beta (ERβ) and NADPH oxidase (NOX), that were screened on bidimensional (2D) and tridimensional (3D) GBM stem cells like (GSC). Our results show that some HDAC inhibitors show antiproliferative properties at 21-32 µM. These results suggest that in this 3D culture, HDACs could be the most relevant targets that are modulated to induce the antiproliferative effects that require in the future further experimental studies.
    Keywords:  3D cell culture; ER; GPER; Glioblastoma multiforme; HDAC; NOX