scholarly journals Epigenetic Modulation by Apabetalone Counters Cytokine-Driven Acute Phase Response In Vitro, in Mice and in Patients with Cardiovascular Disease

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Sylwia Wasiak ◽  
Dean Gilham ◽  
Emily Daze ◽  
Laura M. Tsujikawa ◽  
Christopher Halliday ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Acute Phase ◽  
Acute Phase Response ◽  
Phase Response ◽  
Serum Amyloid ◽  
Cytokine Signaling ◽  
Serum Amyloid P ◽  
Gene And Protein Expression ◽  
Amyloid P

Chronic systemic inflammation contributes to cardiovascular disease (CVD) and correlates with the abundance of acute phase response (APR) proteins in the liver and plasma. Bromodomain and extraterminal (BET) proteins are epigenetic readers that regulate inflammatory gene transcription. We show that BET inhibition by the small molecule apabetalone reduces APR gene and protein expression in human hepatocytes, mouse models, and plasma from CVD patients. Steady-state expression of serum amyloid P, plasminogen activator inhibitor 1, and ceruloplasmin, APR proteins linked to CVD risk, is reduced by apabetalone in cultured hepatocytes and in humanized mouse liver. In cytokine-stimulated hepatocytes, apabetalone reduces the expression of C-reactive protein (CRP), alpha-2-macroglobulin, and serum amyloid P. The latter two are also reduced by apabetalone in the liver of endotoxemic mice. BET knockdown in vitro also counters cytokine-mediated induction of the CRP gene. Mechanistically, apabetalone reduces the cytokine-driven increase in BRD4 BET occupancy at the CRP promoter, confirming that transcription of CRP is BET-dependent. In patients with stable coronary disease, plasma APR proteins CRP, IL-1 receptor antagonist, and fibrinogen γ decrease after apabetalone treatment versus placebo, resulting in a predicted downregulation of the APR pathway and cytokine targets. We conclude that CRP and components of the APR pathway are regulated by BET proteins and that apabetalone counters chronic cytokine signaling in patients.

Major acute phase response of haptoglobin and serum amyloid-P following experimental infection of mice with Trypanosoma brucei brucei

1997 ◽  
Vol 46 (4) ◽  
pp. 247-254 ◽  
Author(s):  
Raphael M. Ngure ◽  
P. David Eckersall ◽  
Francis W. Jennings ◽  
Joanne M. Burke ◽  
Michael J. Stear ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Acute Phase ◽  
Experimental Infection ◽  
Acute Phase Response ◽  
Phase Response ◽  
Serum Amyloid ◽  
Trypanosoma Brucei Brucei ◽  
Serum Amyloid P ◽  
Amyloid P

Abstract 626: Apabetalone (Rvx-208), a Selective Bet Protein Inhibitor, Reduces Expression of Acute Phase Response Markers in vitro and in Patients With Cardiovascular Disease and Chronic Kidney Disease

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Ewelina Kulikowski ◽  
Sylwia Wasiak ◽  
Dean Gilham ◽  
Laura Tsujikawa ◽  
Christopher Halliday ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Chronic Inflammation ◽  
Acute Phase ◽  
Acute Phase Response ◽  
Phase Response ◽  
Serum Amyloid ◽  
Induced Expression ◽  
Amyloid A

Apabetalone is an inhibitor of the epigenetic readers bromodomain and extraterminal (BET) proteins, currently in a phase 3 outcomes trial in patients with cardiovascular disease (CVD) and diabetes mellitus. A post hoc analysis of phase 2b trials demonstrated a 55% relative risk reduction in major adverse cardiac events in CVD patients. Elevated inflammatory markers correlate with CVD. Inflammation also accompanies chronic kidney disease (CKD) and CKD patients are at risk of CVD. Previous research has shown that apabetalone modulates pathways that contribute to chronic inflammation, including the acute phase response (APR). Here, pathway analysis of gene microarrays showed downregulation of APR by apabetalone in primary human hepatocytes (PHH). Real-time PCR and ELISA analysis of RVX-208 treated PHHs confirmed that APR genes that correlate with CVD are suppressed by 20 to 95%, including CRP, ceruloplasmin (CP), serum amyloid P (SAP), PAI-1, alpha 2-macroglobulin (A2M), complement C2, C3 and C5, MBL2, serum amyloid A and interleukin 18. Apabetalone decreased IL-6-induced expression of CP, SAP and A2M, with most striking effects on CRP (-75%). Apabetalone also decreased LPS-induced expression of SAP in a mouse endotoxemia model. To assess effects of apabetalone on inflammatory mediators in CVD patients, SOMAscan™ 1.3K proteomic analysis was performed on plasma from phase 2b ASSERT (12 weeks; n=25) and ASSURE (26 weeks; n=47) clinical trials. This approach identified APR as the top downregulated pathway by apabetalone in both trials. APR biomarkers are elevated in CKD patients where they correlate with disease progression. To gain insight into the pharmacodynamics of the APR response to apabetalone, stage 4 CKD patients (n=8) received a single dose of the drug followed by plasma proteomics at several time points. At 12h post dose, APR was significantly downregulated by apabetalone. Of note, CRP was decreased in CKD patients after 12h of treatment (-7%, p=0.04) versus baseline, as well as in ASSERT (-43%, p=0.01) and ASSURE (-21%, p=0.02) trials versus placebo. Downregulation of the APR pathway by apabetalone may lead to reduced chronic inflammation in CVD and CKD patients and contribute to the reduction in MACE in patients with high residual CVD risk.

The acute phase response and C-reactive protein

2020 ◽  
pp. 2199-2207
Author(s):  
Mark B. Pepys
Keyword(s):  
Acute Phase ◽  
Acute Phase Response ◽  
Serum Amyloid A ◽  
Acute Phase Proteins ◽  
Phase Response ◽  
Serum Amyloid ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Amyloid A ◽  
Serum Amyloid A Protein

The acute phase response—trauma, tissue necrosis, infection, inflammation, and malignant neoplasia induce a complex series of nonspecific systemic, physiological, and metabolic responses including fever, leucocytosis, catabolism of muscle proteins, greatly increased de novo synthesis and secretion of a number of ‘acute phase’ plasma proteins, and decreased synthesis of albumin, transthyretin, and high- and low-density lipoproteins. The altered plasma protein concentration profile is called the acute phase response. Acute phase proteins—these are mostly synthesized by hepatocytes, in which transcription is controlled by cytokines including interleukin 1, interleukin 6, and tumour necrosis factor. The circulating concentrations of complement proteins and clotting factors increase by up to 50 to 100%; some of the proteinase inhibitors and α‎1-acid glycoprotein can increase three- to fivefold; but C-reactive protein (CRP) and serum amyloid A protein (an apolipoprotein of high-density lipoprotein particles) are unique in that their concentrations can change by more than 1000-fold. C-reactive protein—this consists of five identical, nonglycosylated, noncovalently associated polypeptide subunits. It binds to autologous and extrinsic materials which contain phosphocholine, including bacteria and their products. Ligand-bound CRP activates the classical complement pathway and triggers the inflammatory and opsonizing activities of the complement system, thereby contributing to innate host resistance to pneumococci and probably to recognition and safe ‘scavenging’ of cellular debris. Clinical features—(1) determination of CRP in serum or plasma is the most useful marker of the acute phase response in most inflammatory and tissue damaging conditions. (2) Acute phase proteins may be harmful in some circumstances. Sustained increased production of serum amyloid A protein can lead to the deposition of AA-type, reactive systemic amyloid.

scholarly journals Acute Phase Response as a Biological Mechanism‐of‐Action of (Nano)particle‐Induced Cardiovascular Disease

Small ◽  
2020 ◽  
Vol 16 (21) ◽  
pp. 1907476 ◽  
Author(s):  
Niels Hadrup ◽  
Vadim Zhernovkov ◽  
Nicklas Raun Jacobsen ◽  
Carola Voss ◽  
Maximilian Strunz ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Acute Phase ◽  
Mechanism Of Action ◽  
Acute Phase Response ◽  
Phase Response ◽  
Biological Mechanism ◽  
Nano Particle

Serum amyloid A and high density lipoproteins during the acute phase response

1988 ◽  
Vol 18 (6) ◽  
pp. 619-626 ◽  
Author(s):  
LINDA L. BAUSSERMAN ◽  
D. N. BERNIER ◽  
K. P. W. J. McADAM ◽  
P. N. HERBERT
Keyword(s):  
Acute Phase ◽  
Acute Phase Response ◽  
Serum Amyloid A ◽  
High Density ◽  
Phase Response ◽  
Serum Amyloid ◽  
High Density Lipoproteins ◽  
Amyloid A

scholarly journals Acute phase response in the primiparous dairy cows after repeated percutaneous liver biopsy during the transition period

2016 ◽  
Vol 19 (2) ◽  
pp. 393-399 ◽  
Author(s):  
P. Jawor ◽  
A. Brzozowska ◽  
K. Słoniewski ◽  
Z.M. Kowalski ◽  
T. Stefaniak
Keyword(s):  
Body Temperature ◽  
Liver Biopsy ◽  
Dairy Cows ◽  
Acute Phase ◽  
Acute Phase Response ◽  
Serum Amyloid A ◽  
Transition Period ◽  
Phase Response ◽  
Serum Amyloid ◽  
Amyloid A

Abstract The aim of this study was to evaluate the acute phase response of dairy cows to repeated liver biopsy in order to estimate the safety of this procedure during the transition period. Liver biopsies (up to 1000 mg of liver tissue) were conducted twice a day, 7 days before expected parturition and 3 days after calving. The number of needle insertions for each biopsy was recorded and was dependent on the amount of obtained tissue. Blood samples were taken on day 7 before expected parturition, then on days 3, 4, 7 and 14 after calving. Body temperature was measured daily in all 30 cows from day 3 until day 14 after calving. The concentrations of haptoglobin, serum amyloid A, fibrinogen and interleukin-6 were determined in serum and plasma. In 16.7% of cows, the rectal body temperature rose by ≥ 0.5°C on the day after liver biopsy. Although the concentrations of haptoglobin, serum amyloid A and fibrinogen increased significantly after calving (p<0.01), there was no influence of the number of biopsies on the acute phase reaction and repeated biopsy during the transition period had no effect on body temperature. Therefore, the procedure may be regarded as safe for cows during the transition period.

scholarly journals Serum Amyloid P Component Prevents High-Density Lipoprotein-Mediated Neutralization of Lipopolysaccharide

2000 ◽  
Vol 68 (9) ◽  
pp. 4954-4960 ◽  
Author(s):  
Carla J. C. de Haas ◽  
Miriam J. J. G. Poppelier ◽  
Kok P. M. van Kessel ◽  
Jos A. G. van Strijp
Keyword(s):  
Magnetic Beads ◽  
High Density ◽  
Serum Amyloid ◽  
High Density Lipoproteins ◽  
Amyloid P Component ◽  
Serum Amyloid P ◽  
Serum Amyloid P Component ◽  
Amyloid P ◽  
Lps Binding

ABSTRACT Lipopolysaccharide (LPS) is an amphipathic macromolecule that is highly aggregated in aqueous preparations. LPS-binding protein (LBP) catalyzes the transfer of single LPS molecules, segregated from an LPS aggregate, to high-density lipoproteins (HDL), which results in the neutralization of LPS. When fluorescein isothiocyanate-labeled LPS (FITC-LPS) is used, this transfer of LPS monomers to HDL can be measured as an increase in fluorescence due to dequenching of FITC-LPS. Recently, serum amyloid P component (SAP) was shown to neutralize LPS in vitro, although only in the presence of low concentrations of LBP. In this study, we show that SAP prevented HDL-mediated dequenching of FITC-LPS, even in the presence of high concentrations of LBP. Human bactericidal/permeability-increasing protein (BPI), a very potent LPS-binding and -neutralizing protein, also prevented HDL-mediated dequenching of FITC-LPS. Furthermore, SAP inhibited HDL-mediated neutralization of both rough and smooth LPS in a chemiluminescence assay quantifying the LPS-induced priming of neutrophils in human blood. SAP bound both isolated HDL and HDL in serum. Using HDL-coated magnetic beads prebound with SAP, we demonstrated that HDL-bound SAP prevented the binding of LPS to HDL. We suggest that SAP, by preventing LPS binding to HDL, plays a regulatory role, balancing the amount of LPS that, via HDL, is directed to the adrenal glands.

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