Combined Sub-Optimal Doses of Rosuvastatin and Bexarotene Impair Angiotensin II-Induced Arterial Mononuclear Cell Adhesion Through Inhibition of Nox5 Signaling Pathways and Increased RXR/PPARα and RXR/PPARγ Interactions

EscuderoPaula,; MarañónAranzazu, Martinez de; Collado, Aida; González-Navarro, Herminia; Hermenegildo, Carlos; PeiróConcepción,; Piqueras, Laura; Sanz, María-Jesús

doi:10.1089/ars.2014.5969

Cited by 23 publications

(11 citation statements)

References 62 publications

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“…It is important to mention that a possible limitation of this study are the potential interactions, synergisms, or detriments that may arise when studying or implementing novel drugs like SS-31 in a background affected by other medications such as statins. In this sense, previous research has stated that statins can have both detrimental [63,64,65,66] and beneficial effects [67,68,69,70,71,72,73,74,75,76,77], often unrelated to their lipid-lowering effect and rather associated with their pleiotropic actions. The variation of the effect is explained by the type of statin, the dose, the combination with other treatments and the experimental model.…”

Section: Discussionmentioning

confidence: 99%

The Mitochondrial Antioxidant SS-31 Modulates Oxidative Stress, Endoplasmic Reticulum Stress, and Autophagy in Type 2 Diabetes

Escribano-López

Iannantuoni

López‐Domènech

et al. 2019

JCM

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Mitochondrial dysfunction has been shown to play a central role in the pathophysiology of type 2 diabetes (T2D), and mitochondria-targeted agents such as SS-31 are emerging as a promising strategy for its treatment. We aimed to study the effects of SS-31 on leukocytes from T2D patients by evaluating oxidative stress, endoplasmic reticulum (ER) stress and autophagy. Sixty-one T2D patients and 53 controls were included. Anthropometric and analytical measurements were performed. We also assessed reactive oxygen species (ROS) production, calcium content, the expression of ER stress markers GRP78, CHOP, P-eIF2α, and autophagy-related proteins Beclin1, LC3 II/I, and p62 in leukocytes from T2D and control subjects treated or not with SS-31. Furthermore, we have evaluated the action of SS-31 on leukocyte-endothelium interactions. T2D patients exhibited elevated ROS concentration, calcium levels and presence of ER markers (GRP78 and CHOP gene expression, and GRP78 and P-eIF2α protein expression), all of which were reduced by SS-31 treatment. SS-31 also led to a drop in BECN1 gene expression, and Beclin1 and LC3 II/I protein expression in T2D patients. In contrast, the T2D group displayed reduced p62 protein levels that were restored by SS-31. SS-20 (with non-antioxidant activity) did not change any analyzed parameter. In addition, SS-31 decreased rolling flux and leukocyte adhesion, and increased rolling velocity in T2D patients. Our findings suggest that SS-31 exerts potentially beneficial effects on leukocytes of T2D patients modulating oxidative stress and autophagy, and ameliorating ER stress.

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Section: Discussionmentioning

confidence: 99%

The Mitochondrial Antioxidant SS-31 Modulates Oxidative Stress, Endoplasmic Reticulum Stress, and Autophagy in Type 2 Diabetes

Escribano-López

Iannantuoni

López‐Domènech

et al. 2019

JCM

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“…Mononuclear cell recruitment induced by CS was also found to be Nox5 dependent ( 18 ). Additionally, the RhoA/Rho kinase pathway has been implicated in leukocyte recruitment ( 39 ) and RhoA can be activated by Nox5-generated ROS ( 40 ). We show that pharmacological inhibition of RhoA or its knockdown in HUAEC diminished CXCL16 expression provoked by CSE.…”

Section: Discussionmentioning

confidence: 99%

Cigarette Smoke Increases Endothelial CXCL16-Leukocyte CXCR6 Adhesion In Vitro and In Vivo. Potential Consequences in Chronic Obstructive Pulmonary Disease

et al. 2017

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Cardiovascular disease (CVD) is a major comorbidity in chronic obstructive pulmonary disease (COPD). Although the mechanism of its development remains largely unknown, it appears to be associated with cigarette consumption and reduced lung function. Therefore, the aim of this study was to investigate the potential link between water-soluble cigarette smoke extract (CSE)-induced endothelial dysfunction and the function of CXCL16/CXCR6 axis on the initial attachment of leukocytes, in addition to its possible impact on COPD-associated systemic inflammation. To do this, we employed several experimental approaches, including RNA silencing and flow cytometry analysis, the dynamic flow chamber technique, and intravital microscopy in the cremasteric arterioles of animals exposed to cigarette smoke (CS). CSE-induced arterial CXCL16 expression, leading to increased platelet–leukocyte and mononuclear cell adhesiveness. CSE-induced CXCL16 expression was dependent on Nox5 expression and subsequent RhoA/p38 MAPK/NF-κB activation. Flow cytometry analysis revealed that COPD patients (n = 35) presented greater numbers of activated circulating platelets (PAC-1+ and P-selectin+) expressing CXCL16 and CXCR6 as compared with age-matched controls (n = 17), with a higher number of CXCR6+-platelets in the smoking COPD group than in ex-smokers. This correlated with enhanced circulating CXCR6+-platelet–leukocyte aggregates in COPD patients. The increase in circulating numbers of CXCR6-expressing platelets and mononuclear cells resulted in enhanced platelet–leukocyte and leukocyte adhesiveness to CSE-stimulated arterial endothelium, which was greater than that found in age-matched controls and was partly dependent on endothelial CXCL16 upregulation. Furthermore, CS exposure provoked CXCL16-dependent leukocyte–arteriolar adhesion in cremasteric arterioles, which was significantly reduced in animals with a nonfunctional CXCR6 receptor. In conclusion, we provide the first evidence that increased numbers of CXCR6-expressing circulating platelets and mononuclear leukocytes from patients with COPD might be a marker of systemic inflammation with potential consequences in CVD development. Accordingly, CXCL16/CXCR6 axis blockade might constitute a new therapeutic approach for decreasing the risk of CVD in COPD patients.

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“…The present results provided further evidence of the anti-inflammatory capacity of bexarotene by demonstrating that bexarotene significantly inhibited TNF-α-induced expression of IL-6, IL-8 and HMGB1 in FLS. While agonism of RXRs using bexarotene combination therapy has been shown to decrease the expression of MCP-1 in rat mesangial cells and human umbilical arterial endothelial cells (35,36), the present study is the first to demonstrate the ability of bexarotene to exert this effect in FLS. Previous research using a photoaged skin mouse model did not find any significant effect of RXR agonism on ultraviolet-induced expression of MMP-3 and MMP-13.…”

Section: Discussionmentioning

confidence: 62%

Activation of RXR by bexarotene inhibits inflammatory conditions in human rheumatoid arthritis fibroblast‑like synoviocytes

et al. 2019

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Rheumatoid arthritis (RA) is a debilitating joint disease characterized by chronic inflammation, pathologic alteration of fibroblast-like synoviocytes (FLS), destruction of cartilage and bone, and the formation of an invasive pannus. RA-FLS exhibit increased proliferation and resistance to apoptosis. The retinoid X receptor (RXR) has a role in regulating cell cycle, differentiation and apoptosis, and agonism of RXR has been investigated as a treatment strategy in several types of cancer. However, there is little research on the effects of RXR agonism in other diseases. Bexarotene is a novel selective RXR ligand used in the treatment of T-cell lymphoma. In the present study, bexarotene was used to investigate the involvement of RXR in tumor necrosis factor-α (TNF-α)-induced RA conditions in human FLS. To the best of our knowledge, this is the first time that RXR has been demonstrated to be expressed in FLS and to be downregulated in response to TNF-α stimulation. The present study also demonstrated that bexarotene exerted an anti-inflammatory effect by downregulating expression of interleukin (IL)-6, IL-8, monocyte chemoattractant protein-1, and high mobility group box-1. Notably, bexarotene also rescued the TNF-α-induced downregulation of the anti-inflammatory cytokines IL-4 and transforming growth factor-β1. Bexarotene treatment exhibited a potential protective effect against cartilage degradation by downregulating the expression of matrix metalloproteinase (MMP)-1, MMP-3 and MMP-13. In addition, the present results demonstrated that the effects of bexarotene were mediated through the p38 mitogen-activated protein kinase/nuclear factor-κB pathway, via inhibition of p38 protein and the inhibitor α of κB phosphorylation. Taken together, the present findings demonstrated the potential of RXR agonism using bexarotene as a treatment against the development and progression of RA.

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Combined Sub-Optimal Doses of Rosuvastatin and Bexarotene Impair Angiotensin II-Induced Arterial Mononuclear Cell Adhesion Through Inhibition of Nox5 Signaling Pathways and Increased RXR/PPARα and RXR/PPARγ Interactions

Cited by 23 publications

References 62 publications

The Mitochondrial Antioxidant SS-31 Modulates Oxidative Stress, Endoplasmic Reticulum Stress, and Autophagy in Type 2 Diabetes

The Mitochondrial Antioxidant SS-31 Modulates Oxidative Stress, Endoplasmic Reticulum Stress, and Autophagy in Type 2 Diabetes

Cigarette Smoke Increases Endothelial CXCL16-Leukocyte CXCR6 Adhesion In Vitro and In Vivo. Potential Consequences in Chronic Obstructive Pulmonary Disease

Activation of RXR by bexarotene inhibits inflammatory conditions in human rheumatoid arthritis fibroblast‑like synoviocytes

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