Statins and Bempedoic Acid: Different Actions of Cholesterol Inhibitors on Macrophage Activation

Statins represent the most prescribed class of drugs for the treatment of hypercholesterolemia. Effects that go beyond lipid-lowering actions have been suggested to contribute to their beneficial pharmacological properties. Whether and how statins act on macrophages has been a matter of debate. In the present study, we aimed at characterizing the impact of statins on macrophage polarization and comparing these to the effects of bempedoic acid, a recently registered drug for the treatment of hypercholesterolemia, which has been suggested to have a similar beneficial profile but fewer side effects. Treatment of primary murine macrophages with two different statins, i.e., simvastatin and cerivastatin, impaired phagocytotic activity and, concurrently, enhanced pro-inflammatory responses upon short-term lipopolysaccharide challenge, as characterized by an induction of tumor necrosis factor (TNF), interleukin (IL) 1β, and IL6. In contrast, no differences were observed under long-term inflammatory (M1) or anti-inflammatory (M2) conditions, and neither inducible NO synthase (iNOS) expression nor nitric oxide production was altered. Statin treatment led to extracellular-signal regulated kinase (ERK) activation, and the pro-inflammatory statin effects were abolished by ERK inhibition. Bempedoic acid only had a negligible impact on macrophage responses when compared with statins. Taken together, our data point toward an immunomodulatory effect of statins on macrophage polarization, which is absent upon bempedoic acid treatment.

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Magnetic Stimulation Drives Macrophage Polarization in Cell to–Cell Communication with IL-1β Primed Tendon Cells

International Journal of Molecular Sciences ◽

10.3390/ijms21155441 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5441 ◽

Cited By ~ 1

Author(s):

Adriana Vinhas ◽

Ana F. Almeida ◽

Ana I. Gonçalves ◽

Márcia T. Rodrigues ◽

Manuela E. Gomes

Keyword(s):

Inflammatory Responses ◽

Macrophage Polarization ◽

Tendon Repair ◽

Cell Communication ◽

Tendon Healing ◽

Cell Contact ◽

Cellular Interactions ◽

Tendon Cells ◽

Pulsed Electromagnetic ◽

The Impact

Inflammation is part of the natural healing response, but it has been simultaneously associated with tendon disorders, as persistent inflammatory events contribute to physiological changes that compromise tendon functions. The cellular interactions within a niche are extremely important for healing. While human tendon cells (hTDCs) are responsible for the maintenance of tendon matrix and turnover, macrophages regulate healing switching their functional phenotype to environmental stimuli. Thus, insights on the hTDCs and macrophages interactions can provide fundamental contributions on tendon repair mechanisms and on the inflammatory inputs in tendon disorders. We explored the crosstalk between macrophages and hTDCs using co-culture approaches in which hTDCs were previously stimulated with IL-1β. The potential modulatory effect of the pulsed electromagnetic field (PEMF) in macrophage-hTDCs communication was also investigated using the magnetic parameters identified in a previous work. The PEMF influences a macrophage pro-regenerative phenotype and favors the synthesis of anti-inflammatory mediators. These outcomes observed in cell contact co-cultures may be mediated by FAK signaling. The impact of the PEMF overcomes the effect of IL-1β-treated-hTDCs, supporting PEMF immunomodulatory actions on macrophages. This work highlights the relevance of intercellular communication in tendon healing and the beneficial role of the PEMF in guiding inflammatory responses toward regenerative strategies.

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CMR analysis of the cardioprotective effects of chronic statin therapy prior to first STEMI: a propensity score analysis

European Heart Journal ◽

10.1093/eurheartj/ehab724.1461 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

Author(s):

G Mendieta Badimon ◽

M Calvo ◽

J Guzman ◽

P Perez ◽

M Alamar ◽

...

Keyword(s):

Propensity Score ◽

Propensity Score Analysis ◽

Smoking Status ◽

Statin Treatment ◽

Left Ventricular ◽

Prior Treatment ◽

Lipid Lowering ◽

Cardioprotective Effects ◽

The Impact

Abstract Background In addition to their lipid-lowering properties, statins possess cardioprotective effects. However, the impact of the latter on acute cardioprotection and adverse left ventricular (LV) remodelling following ST-elevation myocardial infarction (STEMI) have not been investigated through cardiac magnetic resonance (CMR) analysis to date. Purpose To investigate the cardioprotective effects of chronic oral statin treatment prior to first STEMI. Methods The study included 1236 patients with a first STEMI and a CMR performed during the index admission. Among them, 923 underwent a second CMR at 6 months follow-up. The effects of chronic oral statin treatment prior to STEMI on acute infarct size (IS) as a percentage of LV mass, LV ejection fraction (LVEF), microvascular obstruction (MVO), and changes in LV end-diastolic volume (EDVi) and end-systolic volume indexes (ESVi)] at 6 months were evaluated. A propensity score to receive treatment prior to STEMI with statins was calculated based on the inverse probability of treatment weighting (IPTW) from the following parameters: age on admission, sex, smoking status, type 2 diabetes, hypertension, family history of coronary artery disease, current co-treatments (ACEis/ARBs and/or beta-blockers), heart rate (HR), blood pressure (BP) and creatinine levels on admission, and pre-PCI TIMI flow in the culprit artery. Results were stratified according to a symptom-to-balloon time (S2Bt) ≤ or >3 hours. Results The study population's median age was 59 years (IQR 50–68), 16.3% were women; 18.9% were receiving treatment with statins prior to STEMI (table 1). Despite no effect on MVO occurrence (OR: 0.81 [0.60; 1.09], p=0.166), prior treatment with statins was associated with a reduction in IS (18.43% [16.67; 20.19] vs 21.50% [20.67; 22.34], p=0.002), particularly among subjects with ≤3 hours of S2Bt. Accordingly, prior treatment with statins conferred a benefit in mean baseline LVEF (50.23% [48.73; 51.73] vs 48.15% [47.43; 48.87], p=0.014). At 6 months, treatment with statins prior to STEMI blunted the changes in EDVi and ESVi, but only among patients with ≤3 hours of S2Bt (table 2). In addition, a reduction in the probability of adverse LV remodelling, defined as an increase in ESVi >10%, was observed in statin pre-treated patients (OR: 0.67 [0.45; 0.99], p=0.043). Conclusion Treatment with statins before STEMI is associated with improved indexes of cardioprotection as assessed by CMR, particularly among subjects with S2Bt ≤3 hours. Those effects seem to have an impact in limiting adverse LV remodelling as early as 6 months follow-up, and a greater than 10% change in ESVi. These findings warrant further and prospective evaluation of the potential cardioprotective effects of chronic oral statin treatment prior to STEMI. FUNDunding Acknowledgement Type of funding sources: Other. Main funding source(s): This study was partially funded by several grants from Fundaciό La Marato TV3 (2015 30 31 32), Instituto de Salud Carlos III (FIS15/00531) and La Caixa Banking Foundation (HR17-00527).

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The Impact of Raising the Bar for Clinical Trials in Ulcerative Colitis

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz038 ◽

2019 ◽

Vol 13 (9) ◽

pp. 1217-1226 ◽

Cited By ~ 1

Author(s):

Bruce E Sands ◽

Adam S Cheifetz ◽

Chudy I Nduaka ◽

Daniel Quirk ◽

Wenjin Wang ◽

...

Keyword(s):

Ulcerative Colitis ◽

Clinical Trials ◽

Trial Design ◽

Clinical Trial Design ◽

Regulatory Bodies ◽

Effectiveness Studies ◽

The Impact ◽

Practical Implications ◽

Necrosis Factor

Abstract In order to identify the practical implications for both health care practitioners and patients in understanding differences between the results of trials assessing therapies for ulcerative colitis [UC], we reviewed clinical trials of therapies for moderate to severe UC, with a focus on trial design. Over time, patient populations in UC trials have become more refractory, reflecting that patients are failing treatment with additional and different classes of drug, including conventional therapies, immunosuppressant drugs, and anti-tumour necrosis factor therapies. Outcomes used to measure efficacy have become increasingly stringent in order to meet the expectations of patients and physicians, and the requirements of regulatory bodies. Trial design has also evolved to integrate induction and maintenance therapy phases, so as to facilitate patient recruitment and to answer clinically important questions such as how efficacious therapies are in specific subpopulations of patients and during long-term use. As UC clinical trial design continues to evolve, and with limited head-to-head trials and real-world comparative effectiveness studies evaluating UC therapies, careful judgment is required to appreciate the differences and similarities in trial designs, and to understand how these variances may affect the observed efficacy and safety outcomes.

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The Impact of Tumor Necrosis Factor-α and Interleukin-1β Levels and Polymorphisms on Long-Term Stroke Outcomes

European Neurology ◽

10.1159/000484599 ◽

2017 ◽

Vol 79 (1-2) ◽

pp. 38-44 ◽

Cited By ~ 5

Author(s):

Ju-Wan Kim ◽

Man-Seok Park ◽

Joon-Tae Kim ◽

Hee-Ju Kang ◽

Kyung-Yeol Bae ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Necrosis Factor Alpha ◽

Stroke Outcomes ◽

Tnf Α ◽

Poor Outcomes ◽

Factor Α ◽

The Impact ◽

Necrosis Factor

Background: The accuracy of predictions regarding disability that sets in after stroke could be improved by using blood biomarker measurements. This study aimed to investigate the roles of serum tumor necrosis factor alpha (TNF-α) and interleukin (IL)-1β concentrations and polymorphisms in stroke outcomes. Methods: In total, 286 patients were evaluated at the time of admission and at 2 weeks after stroke, and 222 of these patients (78%) were followed up for 1 year to evaluate the consequences of stroke during both the acute and chronic stages. Stroke outcomes were dichotomized into good and poor using the modified Rankin Scale. Results: The association of TNF-α and IL-1β concentrations and their corresponding genotypes with stroke outcomes was investigated using multivariate logistic regression. Higher TNF-α levels were associated with poor outcomes 1 year after stroke in the presence of the –850T and –308A alleles, and IL-1β levels were associated with poor 1-year stroke outcomes in the presence of the –511T and +3953T alleles. No such associations were found at 2 weeks after stroke. Conclusions: These data provide evidence that serum TNF-α and IL-1β concentrations are related to poor long-term outcomes after stroke in the presence of particular alleles.

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Long-Term Burden of Increased Body Mass Index from Childhood on Adult Dyslipidemia: The i3C Consortium Study

Journal of Clinical Medicine ◽

10.3390/jcm8101725 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1725 ◽

Cited By ~ 1

Author(s):

Yinkun Yan ◽

Lydia A. Bazzano ◽

Markus Juonala ◽

Olli T. Raitakari ◽

Jorma S. A. Viikari ◽

...

Keyword(s):

Body Mass Index ◽

Body Mass ◽

Early Life ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

Lipid Lowering ◽

Lipid Levels ◽

Increased Risk ◽

The Impact

Background: Data are limited regarding the association of cumulative burden and trajectory of body mass index (BMI) from early life with adult lipid disorders. Methods: The study cohort consisted of 5195 adults who had BMI repeatedly measured 4 to 21 times from childhood and had blood lipid measurements of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) and information on lipid-lowering medications in the last adult survey. The area under the curve (AUC) was calculated as a measure of long-term burden (total AUC) and trends (incremental AUC) of BMI. Results: Participants with dyslipidemia, high LDL-C, low HDL-C and high TG had consistently and significantly higher BMI levels from childhood to adulthood compared to those with normal lipid levels. After adjusting for age, race, sex, and cohort, increased risk of adult dyslipidemia was significantly associated with higher values of childhood BMI, adulthood BMI, total AUC and incremental AUC, with odds ratio (95% confidence interval) = 1.22 (1.15–1.29), 1.85 (1.74–1.97), 1.61 (1.52–1.71), and 1.59 (1.50–1.69), respectively, and p < 0.001 for all. The association patterns were similar in most race–sex subgroups. Conclusions: Adults with dyslipidemia versus normal lipid levels have consistently higher levels and distinct life-course trajectories of BMI, suggesting that the impact of excessive body weight on dyslipidemia originates in early life.

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Tumor Necrosis Factor Receptor–associated Factor 6 (TRAF6) Stimulates Extracellular Signal–regulated Kinase (ERK) Activity in CD40 Signaling Along a Ras-independent Pathway

Journal of Experimental Medicine ◽

10.1084/jem.187.2.237 ◽

1998 ◽

Vol 187 (2) ◽

pp. 237-244 ◽

Cited By ~ 82

Author(s):

Masaki Kashiwada ◽

Yumiko Shirakata ◽

Jun-Ichiro Inoue ◽

Hiroyasu Nakano ◽

Kenji Okazaki ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Deletion Mutant ◽

Tumor Necrosis Factor Receptor ◽

Dominant Negative ◽

Erk Activation ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal ◽

Erk Activity ◽

Necrosis Factor

CD40 activates nuclear factor kappa B (NFκB) and the mitogen-activated protein kinase (MAPK) subfamily, including extracellular signal–regulated kinase (ERK). The CD40 cytoplasmic tail interacts with tumor necrosis factor receptor–associated factor (TRAF)2, TRAF3, TRAF5, and TRAF6. These TRAF proteins, with the exception of TRAF3, are required for NFκB activation. Here we report that transient expression of TRAF6 stimulated both ERK and NFκB activity in the 293 cell line. Coexpression of the dominant-negative H-Ras did not affect TRAF6-mediated ERK activity, suggesting that TRAF6 may activate ERK along a Ras-independent pathway. The deletion mutant of TRAF6 lacking the NH2-terminal domain acted as a dominant-negative mutant to suppress ERK activation by full-length CD40 and suppress prominently ERK activation by a deletion mutant of CD40 only containing the binding site for TRAF6 in the cytoplasmic tail (CD40Δ246). Transient expression of the dominant-negative H-Ras significantly suppressed ERK activation by full-length CD40, but marginally suppressed ERK activation by CD40Δ246, compatible with the possibility that TRAF6 is a major transducer of ERK activation by CD40Δ246, whose activity is mediated by a Ras-independent pathway. These results suggest that CD40 activates ERK by both a Ras-dependent pathway and a Ras-independent pathway in which TRAF6 could be involved.

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Extracellular Signal-regulated Kinase Phosphorylates Tumor Necrosis Factor α-converting Enzyme at Threonine 735: A Potential Role in Regulated Shedding

Molecular Biology of the Cell ◽

10.1091/mbc.01-11-0561 ◽

2002 ◽

Vol 13 (6) ◽

pp. 2031-2044 ◽

Cited By ~ 211

Author(s):

Elena Dı́az-Rodrı́guez ◽

Juan Carlos Montero ◽

Azucena Esparı́s-Ogando ◽

Laura Yuste ◽

Atanasio Pandiella

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Converting Enzyme ◽

Erk Activation ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal ◽

Mitogen Activated Protein ◽

Factor Α ◽

Necrosis Factor

The ectodomain of certain transmembrane proteins can be released by the action of cell surface proteases, termed secretases. Here we have investigated how mitogen-activated protein kinases (MAPKs) control the shedding of membrane proteins. We show that extracellular signal-regulated kinase (Erk) acts as an intermediate in protein kinase C-regulated TrkA cleavage. We report that the cytosolic tail of the tumor necrosis factor α-converting enzyme (TACE) is phosphorylated by Erk at threonine 735. In addition, we show that Erk and TACE associate. This association is favored by Erk activation and by the presence of threonine 735. In contrast to the Erk route, the p38 MAPK was able to stimulate TrkA cleavage in cells devoid of TACE activity, indicating that other proteases are also involved in TrkA shedding. These results demonstrate that secretases are able to discriminate between the different stimuli that trigger membrane protein ectodomain cleavage and indicate that phosphorylation by MAPKs may regulate the proteolytic function of membrane secretases.

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Abstract 18157: Impact of Betatrophin (ANGPTL8) R59W Mutation for Future Diabetes, and Minimal Modification of Circulating Betatrophin With Strong Statins

Circulation ◽

10.1161/circ.132.suppl_3.18157 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Atsushi Nohara ◽

Masa-aki Kawashiri ◽

Hiroaki Hattori ◽

Tadao Iwasaki ◽

Jianhui Liu ◽

...

Keyword(s):

Diabetes Mellitus ◽

Lipoprotein Lipase ◽

Statin Treatment ◽

Lipid Lowering ◽

Glucose And Lipid Metabolism ◽

Group 5 ◽

Long Term Impact ◽

Future Diabetes

Betatrophin (ANGPTL8), also known as “Lipasin” (lipoprotein lipase inhibitor), has been reported as a dual-regulator of glucose and lipid metabolism. Functional variant R59W in betatrophin gene is common in Japanese (minor allele 25%) compared with Caucasian (5%). Little is known about long-term impact of this gene variant, and also about the effect of lipid-lowering drugs on this hormone. Methods: A total of 205 cases with dyslipidemia evaluated with baseline 75gOGTT, and post-heparin lipoprotein lipase activities were registered as a long-term cohort. As lipid-lowering trial, a total of 44 patients (Male 21, Age 65±11 ys) with primary dyslipidemia, and 18 genetically confirmed heterozygous familial hypercholesterolemia (FH) (Male 12, Age 65±10 ys,) were analyzed. Non-FH dyslipidemia was treated with 10mg Atorvastatin, and FH was treated with 20mg Rosuvastatin for 8 weeks. Plasma TG and betatrophin levels were log-transformed for statistical analysis. Results: In long-term cohort, 57 cases already showed diabetic pattern at baseline, 148 cases (Male 82, age 56±15 ys, hetero-FH 48 cases, mean follow-up period 10±3 ys) without diabetes at baseline were finally analyzed. Sixty-two cases (42%) developed newly diabetes mellitus during the follow-up, significantly fewer in FH than non-FH (25% vs. 50%, p <0.005). No differences in BMI, fasting glucose, HbA1c in baseline with R59W genotype. In low LPL activity group (n=31), W carriers showed significant increase in HbA1c compared with RR (2.1±0.5 vs. 0.9±0.4 %, p <0.05), but no differences in normal LPL group. In lipid lowering trial, baseline betatrophin levels were lower in FH group (19±13 vs. 13±6 ng/mL, p <0.05), but no difference with/without R59W variant. Statin treatment slightly decreased betatrophin in dyslipidemia group (-4%, p <0.01) and in FH group (-5%, p <0.01). Changes in betatrophin were positively correlated with changes in LDL-C with statins in both groups. Conclusion: Betatrophin R59W variant was a susceptibility factor of future diabetes mellitus with low LPL activity. Baseline betatrophin levels were lower in FH group than other primary dyslipidemia in lipid-lowering trial. Strong statin treatments slightly decreased betatrophin levels, but effect sizes were minimal.

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BAY 11-7082 Is a Broad-Spectrum Inhibitor with Anti-Inflammatory Activity against Multiple Targets

Mediators of Inflammation ◽

10.1155/2012/416036 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 47

Author(s):

Jaehwi Lee ◽

Man Hee Rhee ◽

Eunji Kim ◽

Jae Youl Cho

Keyword(s):

Inflammatory Responses ◽

Janus Kinase ◽

Prostaglandin E ◽

Activator Protein 1 ◽

Toll Like Receptor 4 ◽

Multiple Targets ◽

Extracellular Signal ◽

Inflammatory Drugs ◽

Anti Inflammatory ◽

Necrosis Factor

BAY 11-7082 (BAY) is an inhibitor ofκB kinase (IKK) that has pharmacological activities that include anticancer, neuroprotective, and anti-inflammatory effects. In this study, BAY-pharmacological target pathways were further characterized to determine how this compound simultaneously suppresses various responses. Primary and cancerous (RAW264.7 cells) macrophages were activated by lipopolysaccharide, a ligand of toll-like receptor 4. As reported previously, BAY strongly suppressed the production of nitric oxide, prostaglandin E2, and tumor necrosis factor-αand reduced the translocation of p65, major subunit of nuclear factor-κB, and its upstream signaling events such as phosphorylation of IκBα, IKK, and Akt. In addition, BAY also suppressed the translocation and activation of activator protein-1, interferon regulatory factor-3, and signal transducer and activator of transcription-1 by inhibiting the phosphorylation or activation of extracellular signal-related kinase, p38, TANK-binding protein, and Janus kinase-2. These data strongly suggest that BAY is an inhibitor with multiple targets and could serve as a lead compound in developing strong anti-inflammatory drugs with multiple targets in inflammatory responses.

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Analysis of 5-HT–Induced Short-Term Facilitation at Aplysia Sensorimotor Synapse During Bursts: Increased Synaptic Gain That Does Not Require ERK Activation

Journal of Neurophysiology ◽

10.1152/jn.01261.2004 ◽

2005 ◽

Vol 94 (1) ◽

pp. 871-877 ◽

Cited By ~ 2

Author(s):

Gregg A. Phares ◽

John H. Byrne

Keyword(s):

Synaptic Plasticity ◽

Short Term ◽

Kinetic Measurements ◽

Erk Activation ◽

Synaptic Modulation ◽

Time To Peak ◽

Extracellular Signal ◽

Short And Long Term ◽

Presynaptic Spike

The 5-HT–induced synaptic plasticity of Aplysia sensorimotor synapses has typically been probed by firing a single presynaptic spike. In this study, 5-HT–induced synaptic plasticity was probed with brief bursts of spikes (10 Hz, 1 s), which are more behaviorally relevant stimuli. Because such bursts provide a greater challenge to the release machinery than single spikes, their use may reveal additional aspects of synaptic modulation, and, in particular, the role of extracellular signal-regulated protein kinase (ERK), which has recently been implicated in several examples of short- and long-term synaptic plasticity. Excitatory postsynaptic currents (EPSCs) were characterized by their amplitudes. In addition, two kinetic measurements, time to peak and decay time constant, were determined for the initial and last EPSCs of each burst. Application of 5-HT produced a uniform increase in gain by facilitating each EPSC elicited during a burst of spikes without affecting the kinetics of the initial or last EPSC. These data suggest that short-term facilitation during a burst is mediated largely by processes such as those that affect the size of the releasable pool or rate of vesicle mobilization rather than by an increase in the duration of the presynaptic action potential. An ERK cascade inhibitor (U0126) had no effect on the 5-HT–mediated facilitation of either the initial EPSC or EPSCs elicited late in the burst.

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