Effects of p38 Mitogen-Activated Protein Kinase Inhibition on Vascular and Systemic Inflammation in Patients With Atherosclerosis

Elkhawad, Maysoon; Rudd, James H.F.; Sarov‐Blat, Lea; Cai, Gengqian; Wells, R. J.; Davies, L. Ceri; Collier, David; Marber, Michael; Choudhury, Robin P.; Fayad, Zahi A.; Tawakol, Ahmed; Gleeson, Fergus; Lepore, John J.; Davis, Bill; Willette, Robert N.; Wilkinson, Ian B.; Sprecher, Dennis L.; Cheriyan, Joseph

doi:10.1016/j.jcmg.2012.02.016

Cited by 130 publications

(114 citation statements)

References 34 publications

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“…This reduction is within the range of previously reported changes in aortic FDG uptake following statin therapy, 32 and more recently with a novel p38 mitogen-activated protein kinase inhibitor losmapimod. 20 Interestingly, when the posttreatment aortic TBR was compared with the baseline TBR of CVD patients, it still remained significantly higher. This could be due to a relatively short follow-up period of 8 weeks, and perhaps, a longer follow-up would have shown further reductions in TBR.…”

Section: Mäki-petäjä Et Al Aortic Inflammation In Rheumatoid Arthritimentioning

confidence: 93%

“…Arterial FDG uptake was quantified by using previously published methods 19,20 by a single reader blinded to visit order. In brief, on each 3.27-mm image slice, the maximum standardized uptake values of 18 F-FDG within each region of interest, containing the arterial wall and the lumen, were recorded and divided by background blood FDG concentration in the superior vena cava to yield an arterial maximum target-to-background ratio (TBR max ).…”

Section: Image Analysismentioning

confidence: 99%

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Anti-Tumor Necrosis Factor-α Therapy Reduces Aortic Inflammation and Stiffness in Patients With Rheumatoid Arthritis

et al. 2012

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Background— Rheumatoid arthritis (RA) is a systemic inflammatory condition associated with increased cardiovascular risk. This is not fully explained by traditional risk factors, but direct vascular inflammation and aortic stiffening may play a role. We hypothesized that patients with RA exhibit aortic inflammation, which can be reversed with anti-tumor necrosis factor-α therapy and correlates with aortic stiffness reduction. Methods and Results— Aortic inflammation was quantified in 17 patients with RA, before and after 8 weeks of anti-tumor necrosis factor-α therapy by using 18 F-fluorodeoxyglucose positron emission tomography with computed tomography coregistration. Concomitantly, 34 patients with stable cardiovascular disease were imaged as positive controls at baseline. Aortic fluorodeoxyglucose target-to-background ratios (TBRs) and aortic pulse wave velocity were assessed. RA patients had higher baseline aortic TBRs in comparison with patients who have cardiovascular disease (2.02±0.22 versus 1.74±0.22, P =0.0001). Following therapy, aortic TBR fell to 1.90±0.29, P =0.03, and the proportion of inflamed aortic slices (defined as TBR >2.0) decreased from 50±33% to 33±27%, P =0.03. Also, TBR in the most diseased segment of the aorta fell from 2.51±0.33 to 2.05±0.29, P <0.0001. Treatment also reduced aortic pulse wave velocity significantly (from 9.09±1.77 to 8.63±1.42 m/s, P =0.04), which correlated with the reduction of aortic TBR ( R =0.60, P =0.01). Conclusions— This study demonstrates that RA patients have increased aortic 18 F-fluorodeoxyglucose uptake in comparison with patients who have stable cardiovascular disease. Anti-tumor necrosis factor-α therapy reduces aortic inflammation in patients with RA, and this effect correlates with the decrease in aortic stiffness. These results suggest that RA patients exhibit a subclinical vasculitis, which provides a mechanism for the increased cardiovascular disease risk seen in RA.

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Section: Mäki-petäjä Et Al Aortic Inflammation In Rheumatoid Arthritimentioning

confidence: 93%

Section: Image Analysismentioning

confidence: 99%

Anti-Tumor Necrosis Factor-α Therapy Reduces Aortic Inflammation and Stiffness in Patients With Rheumatoid Arthritis

et al. 2012

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“…MAPKs constitute a family of serine/threonine-specific kinases including ERK, p38 and c-Jun N-terminal kinase (JNK) 12) . In particular, p38 regulates the synthesis of inflammatory mediators at the level of transcription and translation [13][14][15] . On the other hand, ROS can stimulate p38 phosphorylation in a variety of cells, including HUVECs 14,16) .…”

Section: Ldh Gsh and Sod Assaymentioning

confidence: 99%

Luteolin Protects HUVECs from TNF-α-induced Oxidative Stress and Inflammation via its Effects on the Nox4/ROS-NF-κB and MAPK Pathways

Xia

Wang

Jin

et al. 2014

JAT

131

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Aim: Inflammation and oxidative stress are now recognized to be two important contributing factors to the development of atherosclerosis (AS). NADPH oxidase-4 (Nox4)-derived reactive oxygen species (ROS), NF-κB and MAPK play crucial roles in these processes. Luteolin, a flavone rich in many plants, can interrupt the molecular expression and inhibit the progression of inflammation and oxidative stress. The present study was designed to test whether luteolin inhibits TNF-α-induced inflammation and oxidative stress in human umbilical vein endothelial cells (HUVECs) and identify some of the mechanisms underlying these effects.

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“…The GlaxoSmithKline study involving 99 patients has appeared in abstract form and examined 2 dosing regimens with losmapimod at 7.5 mg once daily or 7.5 mg BID in comparison with placebo. 106 Eligibility was based on a tissue-to-background FDG uptake ratio of Ն1.6 in the carotids or ascending aorta. The study failed to reduce the primary end point, which was a reduction in average tissue-to-background FDG uptake.…”

Section: Clinical Trials Of P38 Inhibition For Cardiovascular Indicatmentioning

confidence: 99%

New Therapeutic Targets in Cardiology

2012

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Effects of p38 Mitogen-Activated Protein Kinase Inhibition on Vascular and Systemic Inflammation in Patients With Atherosclerosis

Cited by 130 publications

References 34 publications

Anti-Tumor Necrosis Factor-α Therapy Reduces Aortic Inflammation and Stiffness in Patients With Rheumatoid Arthritis

Anti-Tumor Necrosis Factor-α Therapy Reduces Aortic Inflammation and Stiffness in Patients With Rheumatoid Arthritis

Luteolin Protects HUVECs from TNF-α-induced Oxidative Stress and Inflammation via its Effects on the Nox4/ROS-NF-κB and MAPK Pathways

New Therapeutic Targets in Cardiology

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