Targeting inflammation to reduce cardiovascular disease risk: a realistic clinical prospect?

Welsh, Paul; Grassia, Gianluca; Botha, Shani; Sattar, Naveed; Maffia, Pasquale

doi:10.1111/bph.13818

Cited by 141 publications

(113 citation statements)

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“…These effects include the induction of apoptosis, enhancement of cytokine production, accumulation of inflammatory cells and decrement of myocardial contractility as a consequence of the deterioration in myocardial calcium metabolism 20 . Therefore; blockage of TNF-α has been proposed to be a preventive or alleviating therapeutic target particularly in cardiac pathologies in which inflammation plays a role 21 .…”

Section: ■ Discussionmentioning

confidence: 99%

TNF-alpha inhibitor adalimumab attenuates endotoxin induced cardiac damage in rats

et al. 2020

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Design of the study, acquisition and analysis of data, final approval. ORIGINAL ARTICLE Experimental SurgeryActa Cir Bras. 2020;35(2):e202000202 AbstractPurpose: To investigate the effects of adalimumab pretreatment on the lipopolysaccharide-mediated myocardial injury.Methods: Twenty-eight Wistar rats were randomized into four groups (n=7). Control (C) group animals were injected once a day with intraperitoneal (i.p) 0.9 % saline for two days. In the Adalimumab (Ada) group, adalimumab was injected at a dose of 10 mg/kg/ day (i.p) for two days. Lipopolysaccharide (Lps) group rats were injected with a dose of 5 mg/kg (i.p) lipopolysaccharide. Lipopolysaccharide + Adalimumab (Lps+Ada) group rats received adalimumab before the administration of lipopolysaccharide. The animals were sacrificed 24 h after the last injection and blood samples were obtained for determination of biochemical cardiac injury markers and circulating levels of TNF-α and interleukin-6 (IL-6). Hearts were harvested for histological examination.Results: Endotoxin exposure resulted in significant increases in serum cardiac injury markers, serum cytokines and histological myocardial injury scores in the Lps group. The levels of circulating cytokines, cardiac injury markers and histological injury scores for myocardial necrosis, perivascular cell infiltration, and inflammation were significantly reduced in Lps+Ada as compared to Lps group (p<0.05). Conclusions:Adalimumab pretreatment reduces endotoxin-induced myocardial damage in rats. This beneficial effect is thought to be related to the reduction of cytokine release.

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Section: ■ Discussionmentioning

confidence: 99%

TNF-alpha inhibitor adalimumab attenuates endotoxin induced cardiac damage in rats

et al. 2020

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“…The authors wish to acknowledge that they are co‐authors of the articles by Welsh et al . (), Cirino et al . () and Roviezzo et al .…”

Section: Conflict Of Interestmentioning

confidence: 94%

“…Basic research data strongly support a crucial role played by inflammatory and immune mechanisms in CVD, and studies in animal models have shown that specific immune‐inflammatory pathways could be targeted for therapeutic utility. However, the translation of this scientific knowledge to the treatment of human CVDs is still in the early stages (Welsh et al ., ).…”

Section: Nomenclature Of Targets and Ligandsmentioning

confidence: 97%

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Targeting inflammation to reduce cardiovascular disease risk

Maffia

Cirino

2017

British J Pharmacology

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This joint themed section of the British Journal of Pharmacology and the British Journal of Clinical Pharmacology stems from a joint British Pharmacological Society -Italian Society of Pharmacology symposium held at the 37 th National Congress of the Italian Society of Pharmacology in Naples (Italy) from 27 to 30 October 2015. LINKED ARTICLESThis article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/ 10.1111/bcp.v82.4/issuetoc Abbreviations AT, adipose tissue; ATL, aspirin-triggered lipoxin A4; CVDs, cardiovascular diseases Cardiovascular diseases (CVDs) are the major cause of morbidity and mortality in Western society and, in the near future, are expected to be the main cause of death globally (WHO, 2011). Basic research data strongly support a crucial role played by inflammatory and immune mechanisms in CVD, and studies in animal models have shown that specific immune-inflammatory pathways could be targeted for therapeutic utility. However, the translation of this scientific knowledge to the treatment of human CVDs is still in the early stages (Welsh et al., 2017).New and selective immune therapies are already in use for the treatment of autoimmune diseases, and large clinical trials have just been published or are currently evaluating the effect of several of these treatments on atherosclerosis and related pathologies. The outcome of these studies is likely to lead to new approaches in the management of vascular inflammation.This joint themed section of the British Journal of Pharmacology and the British Journal of Clinical Pharmacology has brought together scientists studying cardiovascular inflammation over a broad range of topics. The aim is to provide an up-todate overview of the current understanding of inflammatory and immune mechanisms in CVD, to summarize the current clinical picture regarding the use of anti-inflammatory drugs in cardiovascular medicine and to discuss future directions towards more specific immune therapies.The themed section is introduced by Welsh et al. (2017). These authors provide an overview of the key therapeutic targets in the treatment of vascular inflammation, placing basic research in a wider clinical perspective. Following the publication of the review article, data from the Phase III Canakinumab Anti-inflammatory Thrombosis Outcomes Study (https://clinicaltrials.gov/ct2/show/NCT01327846) have been published, showing that canakinumab -a monoclonal antibody against IL-1β -in combination with standard therapy reduces recurrent cardiovascular events in patients with a prior myocardial infarction and high levels of circulating C-reactive protein (Ridker et al., 2017). This is the first demonstration in a large, randomized, double-blind, placebo-controlled phase III study that using anti-cytokine-based therapies may be a viable approach for secondary prevention of atherosclerosis-r...

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“…Atherosclerosis is a disease associated with accumulation of cholesterol within macrophages, resulting in the formation of macrophage foam cells, which form the key innate component of the chronic non-resolving inflammatory response that characterises the evolving atherosclerotic plaque [1].…”

Section: Introductionmentioning

confidence: 99%

‘Blow my mind(in)’ – mindin neutralization for the prevention of atherosclerosis?

MacRitchie

Maffia

2018

Clinical Science

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The hallmark features of atherosclerosis include accumulation of low-density lipoprotein (LDL) carrying cholesterol in the vessel wall, formation of lipid-laden foam cells, and the creation of a pro-inflammatory microenvironment. To date, no effective treatments are clinically available for increasing cholesterol efflux from vascular macrophages and inducing reverse cholesterol transport (RCT). In an article published recently in (vol 132, issue 6, 1199-1213), Zhang and colleagues identified the extracellular matrix protein mindin/spondin 2 as a positive regulator of atherosclerosis. Genetic knockout of mindin in apolipoprotein-E (apoE) mice attenuated atherosclerosis, foam cell formation, and inflammation within the vessel wall. Conversely, selective overexpression of mindin in macrophages in apoE mice was sufficient to promote the greater severity of atherosclerosis. Interestingly, foam cell formation was closely associated with the expression of cholesterol transporters (ABCA1 and ACBG1) that facilitate cholesterol efflux. Liver X receptor (LXR)-β is a key modulator of cholesterol transporter expression and formed direct interactions with mindin. Furthermore, the protective effects of mindin deficiency on foam cell formation were blocked by inhibition of LXR-β. This article highlights a novel role of mindin in modulating foam cell formation and atherosclerosis development in mice through direct regulation of LXR-β. Thus far, direct targetting of LXR-β via pharmacological agonists has proven to be problematic due to the lack of subtype selective inhibitors and associated adverse effects. Indirect targetting of LXR-β, therefore, via mindin inhibition offers a new therapeutic strategy for increasing LXR-β induced cholesterol efflux, reducing foam cell formation, and preventing or treating atherosclerosis.

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Targeting inflammation to reduce cardiovascular disease risk: a realistic clinical prospect?

Cited by 141 publications

References 178 publications

TNF-alpha inhibitor adalimumab attenuates endotoxin induced cardiac damage in rats

TNF-alpha inhibitor adalimumab attenuates endotoxin induced cardiac damage in rats

Targeting inflammation to reduce cardiovascular disease risk

‘Blow my mind(in)’ – mindin neutralization for the prevention of atherosclerosis?

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