Silencing of CD40 in vivo reduces progression of experimental atherogenesis through an NF-κB/miR-125b axis and reveals new potential mediators in the pathogenesis of atherosclerosis

Hueso, Miguel; Ramon, Laura de; Navarro, Estanis; Ripoll, Élia; Cruzado, Josep M.; Grinyó, Josep M.; Torrás, Joan

doi:10.1016/j.atherosclerosis.2016.11.002

Cited by 37 publications

(57 citation statements)

References 46 publications

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“…SiRNAmediated inhibition of CD40 in Apoe -/mice reduced atherosclerotic lesions formation, at least partly by limiting CD40-induced NFκB-mediated macrophage activation [73]. However, siRNA-mediated targeting of CD40 also provoked innate immune responses in the kidney, characterized by increased macrophage infiltration and NFκB activation in tubular cells, endothelial cells and infiltrating leukocytes, which may compromise the clinical feasibility of these siRNAs [73,74]. Alternatively, ASO-mediated targeting of CD40 has been investigated and was shown to reduce inflammation and disease severity in experimental models of colitis and nephritis [75,76].…”

Section: The Therapeutic Potential Of Cd40-cd40l In Atherosclerosismentioning

confidence: 97%

“…Antisense oligonucleotides (ASO) and siRNA have also been explored as a strategy to target CD40. SiRNAmediated inhibition of CD40 in Apoe -/mice reduced atherosclerotic lesions formation, at least partly by limiting CD40-induced NFκB-mediated macrophage activation [73]. However, siRNA-mediated targeting of CD40 also provoked innate immune responses in the kidney, characterized by increased macrophage infiltration and NFκB activation in tubular cells, endothelial cells and infiltrating leukocytes, which may compromise the clinical feasibility of these siRNAs [73,74].…”

Section: The Therapeutic Potential Of Cd40-cd40l In Atherosclerosismentioning

confidence: 99%

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The CD40-CD40L Dyad as Immunotherapeutic Target in Cardiovascular Disease

Bosmans

Bosch

Kusters

et al. 2020

J. of Cardiovasc. Trans. Res.

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Chronic inflammation drives the development of atherosclerosis. Despite optimal treatment of classical cardiovascular risk factors, a substantial portion of the population has elevated inflammatory biomarkers and develops atherosclerosis-related complications, indicating that a residual inflammatory risk drives atherosclerotic cardiovascular disease in these patients. Additional anti-inflammatory therapeutic strategies are therefore required. The co-stimulatory molecule CD40 and its ligand CD40L (CD154) have a central role in the regulation of the inflammatory response during the development of atherosclerosis by modulating the interaction between immune cells and between immune cells and non-immune cells. In this review, we discuss the role of the CD40-CD40L dyad in atherosclerosis, and we discuss recent studies on the therapeutic potential of novel CD40-CD40L targeting strategies in cardiovascular medicine.

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Section: The Therapeutic Potential Of Cd40-cd40l In Atherosclerosismentioning

confidence: 97%

Section: The Therapeutic Potential Of Cd40-cd40l In Atherosclerosismentioning

confidence: 99%

The CD40-CD40L Dyad as Immunotherapeutic Target in Cardiovascular Disease

Bosmans

Bosch

Kusters

et al. 2020

J. of Cardiovasc. Trans. Res.

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“…In this context, we have recently described the up-regulation of miR-125b in an experimental model of atherosclerosis progression, as well as in human atherosclerotic plaques [88]. Those changes were reversed upon CD40 silencing [88].…”

Section: 2-de-regulation Of Mirna Expression and Atherosclerosis Prmentioning

confidence: 96%

“…Expression of miR-125b has been also related to the ATH process through its ability to down-regulate the expression of podocalyxin (PODXL), an adhesion molecule of endothelial cells [87]. In this context, we have recently described the up-regulation of miR-125b in an experimental model of atherosclerosis progression, as well as in human atherosclerotic plaques [88]. Those changes were reversed upon CD40 silencing [88].…”

Section: 2-de-regulation Of Mirna Expression and Atherosclerosis Prmentioning

confidence: 99%

 ALUminating the Path of Atherosclerosis Progression: Chaos Theory Suggests a Role for Alu Repeats in the Development of Atherosclerotic Vascular Disease

Hueso

Cruzado

Navarro³

2018

Preprint

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Atherosclerosis (ATH) and Coronary Artery Disease (CAD) are chronic inflammatory diseases with an important genetic background which derive from the cumulative effect of multiple common risk alleles, most of them located in genomic non-coding regions. These complex diseases behave as non-linear dynamical systems that show a high dependence on their initial conditions, so that long-term predictions of disease progression are unreliable. One likely possibility is that the non-linear nature of ATH could be dependent on non-linear correlations in the structure of the human genome. In this review we show how Chaos theory analysis highlighted genomic regions that shared specific structural constraints that could have a role in ATH progression. These regions were shown to be enriched in repetitive sequences of the Alu family, genomic parasites which colonized the human genome, which show a particular secondary structure and have been involved in the regulation of gene expression. We also review the impact of Alu elements on the mechanisms that regulate gene expression, especially highlighting the molecular mechanisms by which the Alu elements could alter the inflammatory homeostasis. We devise especial attention to their relationship with the lncRNA ANRIL, the strongest risk factor for ATH, their role as miRNA sponges, and their ability to interfere with the regulatory circuitry of the NF-kB response. We aim to characterize ATH as a non-linear dynamic system in which small initial alterations in the expression of a number of repetitive elements are somehow amplified to reach phenotypic significance.

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“…Atherosclerosis is up-to-date recognized as a chronic inflammatory disease where lipids, inflammation and immune response in concert contribute to the pathophysiology of the disease [80,81]. IL-1ß has been proposed as a key player linking inflammation to atherogenesis and several other candidates which limit the inflammatory burden of atherosclerosis, as IL-18, CD40/CD40L and CCR2 have been identified [82][83][84][85][86][87][88].…”

Section: Current Scenariomentioning

confidence: 99%

The Interplay of Lipids, Lipoproteins, and Immunity in Atherosclerosis

Pirillo

Bonacina

Norata

et al. 2018

Curr Atheroscler Rep

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Meta-inflammation, a condition of low-grade immune response caused by metabolic dysregulation, immunological memory of innate immune cells (referred to as "trained immunity"), cholesterol homeostasis in dendritic cells, and immunometabolism, i.e., the interplay between immunological and metabolic processes, have all emerged as new actors during atherogenesis. These observations reinforced the interest in directly targeting inflammation to reduce cardiovascular disease. The novel acquisitions in pathophysiology of atherosclerosis reinforce the tight link between lipids, inflammation, and immune response, and support the benefit of targeting LDL-C as well as inflammation to decrease the CVD burden. How this will translate into the clinic will depend on the balance between costs (monoclonal antibodies either to PCSK9 or to IL-1ß), side effects (increased incidence of death due to infections for anti-IL-1ß antibody), and the benefits for patients at high CVD risk.

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Silencing of CD40 in vivo reduces progression of experimental atherogenesis through an NF-κB/miR-125b axis and reveals new potential mediators in the pathogenesis of atherosclerosis

Cited by 37 publications

References 46 publications

The CD40-CD40L Dyad as Immunotherapeutic Target in Cardiovascular Disease

The CD40-CD40L Dyad as Immunotherapeutic Target in Cardiovascular Disease

ALUminating the Path of Atherosclerosis Progression: Chaos Theory Suggests a Role for Alu Repeats in the Development of Atherosclerotic Vascular Disease

The Interplay of Lipids, Lipoproteins, and Immunity in Atherosclerosis

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Silencing of CD40 in vivo reduces progression of experimental atherogenesis through an NF-κB/miR-125b axis and reveals new potential mediators in the pathogenesis of atherosclerosis

Cited by 37 publications

References 46 publications

The CD40-CD40L Dyad as Immunotherapeutic Target in Cardiovascular Disease

The CD40-CD40L Dyad as Immunotherapeutic Target in Cardiovascular Disease

&nbsp;ALUminating the Path of Atherosclerosis Progression: Chaos Theory Suggests a Role for Alu Repeats in the Development of Atherosclerotic Vascular Disease

The Interplay of Lipids, Lipoproteins, and Immunity in Atherosclerosis

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ALUminating the Path of Atherosclerosis Progression: Chaos Theory Suggests a Role for Alu Repeats in the Development of Atherosclerotic Vascular Disease