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

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.

scholarly journals Particle-induced pulmonary acute phase response may be the causal link between particle inhalation and cardiovascular disease

2014 ◽  
Vol 6 (6) ◽  
pp. 517-531 ◽  
Author(s):  
Anne T. Saber ◽  
Nicklas R. Jacobsen ◽  
Petra Jackson ◽  
Sarah Søs Poulsen ◽  
Zdenka O. Kyjovska ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Acute Phase ◽  
Acute Phase Response ◽  
Causal Link ◽  
Phase Response ◽  
Particle Inhalation

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.

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