scholarly journals The BET Protein Inhibitor Apabetalone Rescues Diabetes-induced Impairment of Angiogenic Response by Epigenetic Regulation of Thrombospondin-1

2021 ◽  
Author(s):  
Shafeeq Ahmed Mohammed ◽  
Mattia Albiero ◽  
Samuele Ambrosini ◽  
Era Gorica ◽  
Gergely Karsai ◽  
...  
Keyword(s):  
Epigenetic Regulation ◽  
Protein Inhibitor ◽  
Angiogenic Response ◽  
Thrombospondin 1 ◽  
Bet Protein

scholarly journals Superior efficacy of cotreatment with BET protein inhibitor and BCL2 or MCL1 inhibitor against AML blast progenitor cells

2019 ◽  
Vol 9 (2) ◽  
Author(s):  
Warren Fiskus ◽  
Tianyu Cai ◽  
Courtney D. DiNardo ◽  
Steven M. Kornblau ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Protein Inhibitor ◽  
Superior Efficacy ◽  
Bet Protein

FP330APABETALONE, A SELECTIVE BROMODOMAIN AND EXTRA-TERMINAL (BET) PROTEIN INHIBITOR, REDUCES SERUM FGF23 IN CARDIOVASCULAR DISEASE AND CHRONIC KIDNEY DISEASE PATIENTS

2019 ◽  
Vol 34 (Supplement_1) ◽  
Author(s):  
Kamyar Kalantar-Zadeh ◽  
Carmine Zoccali ◽  
Srinivasan Beddhu ◽  
Vincent Brandenburg ◽  
Mathias Haarhaus ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Protein Inhibitor ◽  
Bet Protein

scholarly journals BET protein inhibitor JQ1 inhibits growth and modulates WNT signaling in mesenchymal stem cells

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Saeed Alghamdi ◽  
Irfan Khan ◽  
Naimisha Beeravolu ◽  
Christina McKee ◽  
Bryan Thibodeau ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Wnt Signaling ◽  
Protein Inhibitor ◽  
Bet Protein

scholarly journals SP071APABETALONE (RVX-208), A SELECTIVE BROMODOMAIN AND EXTRA-TERMINAL (BET) PROTEIN INHIBITOR, DECREASES ABUNDANCE AND ACTIVITY OF COMPLEMENT PROTEINS IN VITRO, IN MICE AND IN CLINICAL STUDIES

2016 ◽  
Vol 31 (suppl_1) ◽  
pp. i109-i109 ◽  
Author(s):  
Norman Cw Wong ◽  
Kamyar Kalantar-Zadeh ◽  
Ewelina Kulikowski ◽  
Sylwia Wasiak ◽  
Dean Gilham ◽  
...  
Keyword(s):  
Clinical Studies ◽  
Protein Inhibitor ◽  
Complement Proteins ◽  
Bet Protein

scholarly journals Downregulation of the Complement Cascade In Vitro, in Mice and in Patients with Cardiovascular Disease by the BET Protein Inhibitor Apabetalone (RVX-208)

2017 ◽  
Vol 10 (4) ◽  
pp. 337-347 ◽  
Author(s):  
Sylwia Wasiak ◽  
Dean Gilham ◽  
Laura M. Tsujikawa ◽  
Christopher Halliday ◽  
Cyrus Calosing ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Complement Cascade ◽  
Protein Inhibitor ◽  
Bet Protein

scholarly journals The BET protein inhibitor apabetalone (RVX-208) restores angiogenic response in type 1 and type 2 diabetes by transcriptional regulation of thrombospondin-1

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
S Mohammed ◽  
M A Mattia ◽  
G K Gergely ◽  
G S Gaia ◽  
S A Ambrosini ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Blood Flow ◽  
Gastrocnemius Muscle ◽  
Tube Formation ◽  
Public Institution ◽  
Diabetic Patients ◽  
Angiogenic Response ◽  
Bet Protein ◽  
The Impact

Abstract Background Peripheral artery disease (PAD) is highly prevalent in people with type 2 diabetes and associates with chronic limb ischemia and poor prognosis. Understanding the mechanisms of impaired blood vessel growth in diabetic patients is of paramount importance to develop new angiogenic therapies in this setting. Dysregulation of epigenetic mechanisms of gene transcription in vascular cells contributes to cardiovascular disease development but is currently not targeted by therapies. Apabetalone (RVX-208) – an FDA approved small molecule inhibitor of the epigenetic readers bromodomain and extra-terminal (BET) proteins – has recently shown to modulate transcriptional programs implicated in vascular inflammation and atherosclerosis. Purpose To investigate RVX-208 effects in modulating angiogenic response and post-ischemic vascularization in diabetes. Methods Primary human aortic endothelial cells (HAECs) were exposed to normal glucose (NG, 5 mM) or high glucose (HG, 20 mM) for 48 hours in presence of RVX-208 (20μM) or vehicle (DMSO). Scratch and tube formation assays were performed to investigate the impact of RVX-208 on angiogenic properties of HAECs. T1D mice (streptozotocin-induced diabetes) and T2D mice (Lepdb/db) were orally treated with apabetalone or vehicle for 5 days. Hindlimb ischemia was induced in T1D mice & blood flow recovery analysed at 30 minutes, 7 and 14 days by laser Doppler imaging. Sprouting and matrigel plug assays were performed in Lepdb/db mice. Gastrocnemius muscle samples from patients with and without T2D were employed to translate our experimental findings. Results HG impaired HAECs migration and tube formation as compared to NG, whereas treatment with RVX-208 rescued HG-induced impairment of angiogenic properties. Real time PCR arrays in HG-treated HAECs showed that RVX-208 treatment prevents the dysregulation of genes implicated in endothelial migration, sprouting and inflammation, namely the anti-angiogenic molecule thrombospondin (THBS1), VEGF-A, IL-1β, IL-6, VCAM-1, and CXCL1. Of interest, both gene silencing of BET protein (BRD4) or its pharmacological inhibition by RVX-208 reduced THBS1 expression while restoring VEGFA levels in HG-treated HAECs. ChIP assays showed the enrichment of both BRD4 and the active chromatin mark H3K27Ac on THBS1 promoter. Mechanistic experiments uncovered the inhibitory role of THBS1 on VEGFA signalling, as also confirmed by STRING analysis. Treatment of T1D mice with RVX-208 improved blood flow reperfusion and vascular density at 14 days as compared to vehicle-treated animals. Moreover, RVX-208 restored endothelial sprouting in T2D-Lepdb/db mice. Of clinical relevance, THBS1 was upregulated while VEGFA expression was reduced in gastrocnemius muscle specimens from T2D patients with PAD as compared to non-diabetic controls. Conclusion In vivo targeting of BET-proteins by RVX-208 may represents a novel therapeutic approach to boost post-ischemic neovascularization in diabetes. FUNDunding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): University of Zurich

Abstract A093: Phase 1/2 study of INCB054329, a bromodomain and extraterminal (BET) protein inhibitor, in patients (pts) with advanced malignancies

2018 ◽  
Author(s):  
Gerald Falchook ◽  
Moshe Talpaz ◽  
Monica Mita ◽  
Russ Szmulewitz ◽  
Sarina Piha-Paul ◽  
...  
Keyword(s):  
Phase 1 ◽  
Protein Inhibitor ◽  
Advanced Malignancies ◽  
Bet Protein

Apabetalone, a selective BET protein inhibitor, reduces ischemic cardiovascular events and hospitalization for heart failure in patients with acute coronary syndrome and type 2 diabetes

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
K.K Ray ◽  
S.J Nicholls ◽  
K.A Buhr ◽  
H.N Ginsberg ◽  
K Kalantar-Zadeh ◽  
...  
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Acute Coronary Syndrome ◽  
Number Needed To Treat ◽  
Funding Source ◽  
Protein Inhibitor ◽  
Private Company ◽  
Coronary Syndrome ◽  
Bet Protein

Abstract Background Despite established treatments, patients with type 2 diabetes mellitus (T2DM) and acute coronary syndrome (ACS) are at higher risk of ischemic cardiovascular (CV) events and hospitalization for heart failure (HHF) compared to those without T2DM. LDL-C lowering or use of GLP-1 agonists predominantly affects ischemic CV events, with little effect on HHF. Conversely, treatment with SGLT-2 inhibitors reduces HHF, with less effect on ischemic CV events. Preclinical studies indicate that bromodomain and extra-terminal (BET) proteins coordinate gene transcription for pathways that promote atherothrombotic events as well as heart failure. We assessed the clinical effect of apabetalone (APB), a novel BET protein inhibitor, on a composite of non-fatal ischemic CV events, HHF, and CV death in a post hoc analysis of the BETonMACE trial Methods BETonMACE was a double-blind, placebo-controlled phase 3 study in patients with T2DM and recent acute coronary syndrome receiving standard of care risk factor management. In 13 countries, 2425 patients were enrolled. We conducted a time-to-event analysis for first adjudicated CV death or non-fatal MI, stroke, or HHF using a log-rank test and Cox proportional hazards model. Results At baseline median age was 62 years, 25.6% were female, 87.6% white, and use of high intensity statin, ACE inhibitors/ angiotensin II blockers, dual antiplatelet therapy and beta blocker were 90, 88, 92 and 91% respectively. A total of 312 subjects had an endpoint event, with 139 (11.5%) patients in the ABP group and 173 (14.3%) among PBO (HR 0.78, 95% CI 0.63–0.98, p=0.03, Figure). At 26 months, the absolute risk reduction was 3.2% and number needed to treat was 31. Numerically favorable HRs were observed for each component endpoint except for stroke (Table). Conclusion This present analysis suggests that BET inhibition with APB may be a novel pathway through which to reduce both HHF and ischemic CV events in high risk patients with T2DM thus impacting broader clinical outcomes with potentially large benefits for patients and healthcare systems. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Resverlogix Corp

scholarly journals Angiogenic response to passive movement and active exercise in individuals with peripheral arterial disease

2013 ◽  
Vol 115 (12) ◽  
pp. 1777-1787 ◽  
Author(s):  
B. Hoier ◽  
M. Walker ◽  
M. Passos ◽  
P. J. Walker ◽  
A. Green ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Peripheral Arterial Disease ◽  
Arterial Disease ◽  
Passive Movement ◽  
Vegf Receptor ◽  
Tissue Samples ◽  
Angiogenic Response ◽  
Control Subjects ◽  
Thrombospondin 1 ◽  
Peripheral Arterial

Peripheral arterial disease (PAD) is caused by atherosclerosis and is associated with microcirculatory impairments in skeletal muscle. The present study evaluated the angiogenic response to exercise and passive movement in skeletal muscle of PAD patients compared with healthy control subjects. Twenty-one PAD patients and 17 aged control subjects were randomly assigned to either a passive movement or an active exercise study. Interstitial fluid microdialysate and tissue samples were obtained from the thigh skeletal muscle. Muscle dialysate vascular endothelial growth factor (VEGF) levels were modestly increased in response to either passive movement or active exercise in both subject groups. The basal muscle dialysate level of the angiostatic factor thrombospondin-1 protein was markedly higher ( P < 0.05) in PAD patients compared with the control subjects, whereas soluble VEGF receptor-1 dialysate levels were similar in the two groups. The basal VEGF protein content in the muscle tissue samples was ∼27% lower ( P < 0.05) in the PAD patients compared with the control subjects. Analysis of mRNA expression for a range of angiogenic and angiostatic factors revealed a modest change with active exercise and passive movement in both groups, except for an increase ( P < 0.05) in the ratio of angiopoietin-2 to angiopoietin-1 mRNA in the PAD group with both interventions. PAD patients and aged individuals showed a similar limited angiogenic response to active exercise and passive movement. The limited increase in muscle extracellular VEGF combined with an elevated basal level of thrombospondin-1 in muscle extracellular fluid of PAD patients may restrict capillary growth in these patients.

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