Rationale and design of the LosmApimod To Inhibit p38 MAP kinase as a TherapeUtic target and moDify outcomes after an acute coronary syndromE trial

O’Donoghue, Michelle L.; Glaser, Ruchira; Aylward, Philip E.; Cavender, Matthew A.; Crisp, Adam; Fox, Keith A.A.; Laws, Ian; López‐Sendón, José; Steg, Philippe Gabriel; Théroux, Pierre; Sabatine, Marc S.; Morrow, David A.

doi:10.1016/j.ahj.2015.02.012

Cited by 30 publications

(27 citation statements)

References 23 publications

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“…An inhibitor of p38 MAP kinase (losmapimod) likewise failed to reduce cardiovascular events in secondary prevention. Oxidative stress also activates p38 MAP kinase, and its inhibition does not interfere selectively with the IL-6 pathway causally implicated in cardiovascular events (84,85). …”

Section: Beyond Cantos: Other Targets Other Indicationsmentioning

confidence: 99%

Interleukin-1 Beta as a Target for Atherosclerosis Therapy

Libby

2017

Journal of the American College of Cardiology

509

350

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Inflammatory pathways drive atherogenesis and link traditional risk factors to atherosclerosis and its complications. One inflammatory mediator has come to the fore as a therapeutic target in cardiovascular disease. The experimental and clinical evidence reviewed here support interleukin-1 beta (IL-1β) as both a local vascular and systemic contributor in this regard. Intrinsic vascular wall cells and lesional leukocytes alike can produce this cytokine. Local stimuli in the plaque favor the generation of active IL-1β through the action of a molecular assembly known as the inflammasome. Clinically applicable interventions that interfere with IL-1 action can improve cardiovascular outcomes, ushering in a new era of anti-inflammatory therapies for atherosclerosis. The translational path described here illustrates how advances in basic vascular biology may transform therapy. Biomarker-directed application of anti-inflammatory interventions promises to help us achieve a more precise and personalized allocation of therapy for our cardiovascular patients.

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Section: Beyond Cantos: Other Targets Other Indicationsmentioning

confidence: 99%

Interleukin-1 Beta as a Target for Atherosclerosis Therapy

Libby

2017

Journal of the American College of Cardiology

509

350

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“…LATITUDE-TIMI 60 was a two-part trial. An initial cohort (A) of 3,503 patients would be randomized to the treatment drug or placebo in a double-blinded fashion, and if safety and efficacy were demonstrated, a second cohort (B) of approximately 22,000 patients would then be randomized (12). This was an international study involving 322 sites in 34 countries.…”

Section: The Recently Published Results Of Latitude-timi 60 (Effect Omentioning

confidence: 99%

“…This was an international study involving 322 sites in 34 countries. Eligible patients were those presenting with non-ST segment elevation myocardial infarction (NSTEMI) within 24 hours of symptoms, or ST-segment elevation myocardial infarction (STEMI) within 12 hours of onset (12). The treatment arm received 7.5 mg of losmapimod orally twice daily, started at the time of study enrollment (prior to PCI) and continued for 12 weeks.…”

Section: The Recently Published Results Of Latitude-timi 60 (Effect Omentioning

confidence: 99%

Losmapimod does not reduce cardiovascular events in patients with acute myocardial infarction

Aronow

Kaple

2016

J. Thorac. Dis.

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“…ANOVA, analysis of variance; IL-6, interleukin-6; miR-9, microRNA 9; NC, negative control; OLR1, oxidized low-density lipoprotein receptor 1; TNF-α, tumor necrosis factor-alpha; VEGF, vascular endothelial growth factor 3.7 | Upregulated miR-9 inhibits the protein level of OLR1 and the p38MAPK signaling pathway-related proteins In addition, several previous studies have demonstrated that the p38MAPK signaling pathway is related to ACS, [25][26][27] and miR-9 could modulate the MAPK signaling pathway. Panel A, the content of TNF-α in mice serum in each group; Panel B, the content of IL-6 in mice serum in each group; Panel C, the content of VEGF in mice serum in each group; *p < 0.05 versus the control group, #p < 0.05 versus the atherosclerosis group.…”

Section: Upregulated Mir-9 Decreasesmentioning

confidence: 99%

“…The results indicated that upregulated miR-9 could inhibit OLR1 and p38MAPK signaling pathway. In addition, several previous studies have demonstrated that the p38MAPK signaling pathway is related to ACS, [25][26][27] and miR-9 could modulate the MAPK signaling pathway. 28 These findings revealed that miR-9 could regulate OLR1 and p38MAPK signaling pathway in ACS.…”

Section: Upregulated Mir-9 Inhibits Serum Levels Of Tnf-α Il-6 Anmentioning

confidence: 99%

MicroRNA‐9 overexpression suppresses vulnerable atherosclerotic plaque and enhances vascular remodeling through negative regulation of the p38MAPK pathway via OLR1 in acute coronary syndrome

Wang

Huang

et al. 2019

J of Cellular Biochemistry

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Acute coronary syndrome (ACS) is characterized by atherosclerotic plaque rupture with a high incidence of recurrent ischemic events. Several microRNAs are found to be aberrantly expressed in atherosclerotic plaques. This study aims to investigate the effects of microRNA‐9 (miR‐9) on vulnerable atherosclerotic plaque and vascular remodeling in ACS and underlying mechanisms. Microarray‐based gene expression profiling was used to identify differentially expressed genes related to ACS and regulatory miRNAs. Oxidized low‐density lipoprotein (lectin‐like) receptor 1 (OLR1) was identified to be aberrantly activated in ACS and regulated by miR‐9. OLR1 was verified as a target gene of miR‐9 by bioinformatics prediction and dual luciferase reporter gene assay. The atherosclerotic models were induced in ApoE−/− mice, in which the agomir or antagomir of miR‐9, or small interfering RNA (siRNA) against OLR1 were separately introduced. Serum lipid levels and expression of vascular remodeling and inflammatory response‐related factors were determined, respectively. On the basis of the obtained results, in the atherosclerosis mice treated with the agomir of miR‐9 and siRNA against OLR1, the p38‐mitogen‐activated protein kinase (p38MAPK) pathway was inhibited; levels of triglyceride, total cholesterol, low‐density lipoprotein cholesterol, tumor necrosis factor‐α, interleukin‐6, and vascular endothelial growth factor were reduced, but the high‐density lipoprotein cholesterol level was increased, along with decreased vulnerable atherosclerotic plaque area and enhanced vascular remodeling. Taken together, these findings suggested an inhibitory role miR‐9 acts in the formation of vulnerable atherosclerotic plaques in ACS mice, along with a promoted vascular remodeling, via a negative feedback regulation of OLR1‐mediated p38MAPK pathway.

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Rationale and design of the LosmApimod To Inhibit p38 MAP kinase as a TherapeUtic target and moDify outcomes after an acute coronary syndromE trial

Cited by 30 publications

References 23 publications

Interleukin-1 Beta as a Target for Atherosclerosis Therapy

Interleukin-1 Beta as a Target for Atherosclerosis Therapy

Losmapimod does not reduce cardiovascular events in patients with acute myocardial infarction

MicroRNA‐9 overexpression suppresses vulnerable atherosclerotic plaque and enhances vascular remodeling through negative regulation of the p38MAPK pathway via OLR1 in acute coronary syndrome

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