Apabetalone lowers serum alkaline phosphatase and improves cardiovascular risk in patients with cardiovascular disease

Haarhaus, Mathias; Ray, Kausik K.; Nicholls, Stephen J.; Schwartz, Gregory G.; Kulikowski, Ewelina; Johansson, Jan; Sweeney, Michael; Halliday, Christopher; Lebioda, Kenneth; Wong, Norman C.W.; Brandenburg, Vincent; Beddhu, Srinivasan; Tonelli, Marcello; Zoccali, Carmine; Kalantar-Zadeh, Kamyar

doi:10.1016/j.atherosclerosis.2019.09.002

Cited by 31 publications

(35 citation statements)

References 43 publications

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“…In this study, we demonstrate that apabetalone suppresses TNAP expression in liver cells (Supplemental Figs. 1A-B), the major source of circulating TNAP [26], which is consistent with reduced serum ALP observed in patients receiving apabetalone [13,14]. The present study also shows that apabetalone or JQ1 attenuates TNAP gene expression, protein levels and enzyme activity in VSMCs during osteogenic transdifferentiation (Figs.…”

Section: Discussionsupporting

confidence: 89%

“…In CKD patients, apabetalone had favorable effects on kidney function evaluated by estimated glomerular filtration rate [13]. Apabetalone also reduced circulating alkaline phosphatase (ALP), a robust and independent predictor of all-cause mortality that contributes to VC progression [13,14]. Notably, a single dose provided to CKD patients rapidly resulted in reduction of several inflammatory cytokines, including IL-6 [15].…”

Section: Introductionmentioning

confidence: 99%

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Apabetalone downregulates factors and pathways associated with vascular calcification

et al. 2019

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and extraterminal (BET) proteins are implicated in VSMC transdifferentiation and calcification. • Apabetalone, a BET inhibitor, prevents calcification of VSMCs by regulating expression of key factors. • BET protein BRD4 may cooperate with 7 specific transcription factors (TFs) to promote transdifferentiation and calcification. • Apabetalone is a promising therapeutic for pathological vascular calcification.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Apabetalone downregulates factors and pathways associated with vascular calcification

et al. 2019

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“…3,32,35,52,215,216 Moreover, clinical data collected to date show that safety is not a limiting factor for chronic dosing of apabetalone, supporting the use of BD2selective BETi in diseases outside of cancer. 32,214,215 Second, apabetalone trials have identified key pathways that benefit from BD2-selective BETi in cardiovascular and diabetes mellitus patients, 18,20,32,43,44,46 as well as chronic kidney disease patients. 47,217 This further underscores the role of BET proteins in driving the chronic maladaptive overexpression of genes and proteins which participate in networks and pathways that directly contribute to these disease states.…”

Section: Bd-selective Beti In the Clinic: What Human Data Do We Have?mentioning

confidence: 99%

“…Evidence is mounting to support the use of BETi in treating cancer, metabolic, inflammatory, neurologic, cardiovascular, and musculoskeletal diseases. [1][2][3]14,19,20,29,31,44,[50][51][52][53][54][55][56][57][58][59][60][61][62] Investigation of BETi potential as an antiviral has also recently garnered interest. [63][64][65][66][67] Unlike other reviews in the field, we focus this review on explaining why targeting BET proteins shows potential benefit in seemingly unrelated disease states.…”

Section: Introductionmentioning

confidence: 99%

Inhibitors of bromodomain and extra‐terminal proteins for treating multiple human diseases

Kulikowski

Rakai

Wong

2020

Medicinal Research Reviews

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Clinical development of bromodomain and extra‐terminal (BET) protein inhibitors differs from the traditional course of drug development. These drugs are simultaneously being evaluated for treating a wide spectrum of human diseases due to their novel mechanism of action. BET proteins are epigenetic “readers,” which play a primary role in transcription. Here, we briefly describe the BET family of proteins, of which BRD4 has been studied most extensively. We discuss BRD4 activity at latent enhancers as an example of BET protein function. We examine BRD4 redistribution and enhancer reprogramming in embryonic development, cancer, cardiovascular, autoimmune, and metabolic diseases, presenting hallmark studies that highlight BET proteins as attractive targets for therapeutic intervention. We review the currently available approaches to targeting BET proteins, methods of selectively targeting individual bromodomains, and review studies that compare the effects of selective BET inhibition to those of pan‐BET inhibition. Lastly, we examine the current clinical landscape of BET inhibitor development.

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“…RVX-208 counters the trans-differentiation and calcification of VSMCs [190]. RVX-208 lowers serum alkaline phosphatase levels and improves CVD risk [191]. RVX-208 favorably modulates the vulnerability of carotid artery plaque through ultrasonic measurement, which is related to an increase of HDL-P levels [192].…”

Section: Rvx-208 (Apabetalone)mentioning

confidence: 99%

High-Density Lipoprotein: From Biological Functions to Clinical Perspectives

Liu¹

2020

Apolipoproteins, Triglycerides and Cholesterol

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High-density lipoprotein (HDL) is a heterogeneous particle composed of apolipoproteins, enzymes, and lipids. Besides transporting cholesterol to the liver, HDL also exerts many protections on anti-oxidation, anti-inflammation, and anti-apoptosis. Initial understandings of HDL came from its protective roles against atherosclerosis and the observation that high plasma HDL cholesterol (HDL-C) levels seemed to decrease cardiovascular disease (CVD) attack. However, those patients either with cholesterol ester transfer protein (CETP) deficiency or taking CETP inhibitors substantially elevated HDL-C levels but did not necessarily decrease CVD risk. Thus, some researchers suggested that quantitative measurements of HDL particle (HDL-P) might be more valuable than traditional HDL-C measurements. What is more bewildering is that HDL from patients with systemic inflammation decreased its protective effects and even became a pro-inflammatory factor. Recently, synthesized HDL and apolipoprotein mimetic peptides showed biological functions similar to native ones. Expectedly, lots of novel measurement methods and therapeutic agents about HDL would be established soon.

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Apabetalone lowers serum alkaline phosphatase and improves cardiovascular risk in patients with cardiovascular disease

Cited by 31 publications

References 43 publications

Apabetalone downregulates factors and pathways associated with vascular calcification

Apabetalone downregulates factors and pathways associated with vascular calcification

Inhibitors of bromodomain and extra‐terminal proteins for treating multiple human diseases

High-Density Lipoprotein: From Biological Functions to Clinical Perspectives

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