Complex association of lipoprotein(a) with aortic stenosis

Rogers, Maximillian A.; Aikawa, Elena

doi:10.1136/heartjnl-2019-316498

Cited by 3 publications

(2 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…At the same time, crenigacestat causes downregulation of the proteins, specific for osteogenic differentiation, COL1A1 and SPARC as well as downregulation of Runx2 expression and suppression of ECM mineralization. Other downregulated proteins are also associated with osteogenic differentiation, e.g., A2M was identified to be marker of later, calcific stage of CAVD according to spatiotemporal multi-omics data ( 33 ); IGF2R is involved in vascular calcification through Erk1/2 and Akt signaling ( 34 ); apolipoprotein CIII (APOC3) is associated with CAVD progression ( 35 ).…”

Section: Discussionmentioning

confidence: 99%

Crenigacestat (LY3039478) inhibits osteogenic differentiation of human valve interstitial cells from patients with aortic valve calcification in vitro

Lobov

Boyarskaya²,

Kachanova³

et al. 2022

Front. Cardiovasc. Med.

View full text Add to dashboard Cite

Calcific aortic valve disease (CAVD) is one of the dangerous forms of vascular calcification. CAVD leads to calcification of the aortic valve and disturbance of blood flow. Despite high mortality, there is no targeted therapy against CAVD or vascular calcification. Osteogenic differentiation of valve interstitial cells (VICs) is one of the key factors of CAVD progression and inhibition of this process seems a fruitful target for potential therapy. By our previous study we assumed that inhibitors of Notch pathway might be effective to suppress aortic valve leaflet calcification. We tested CB-103 and crenigacestat (LY3039478), two selective inhibitors of Notch-signaling, for suppression of osteogenic differentiation of VICs isolated from patients with CAVD in vitro. Effect of inhibitors were assessed by the measurement of extracellular matrix calcification and osteogenic gene expression. For effective inhibitor (crenigacestat) we also performed MTT and proteomics study for better understanding of its effect on VICs in vitro. CB-103 did not affect osteogenic differentiation. Crenigacestat completely inhibited osteogenic differentiation (both matrix mineralization and Runx2 expression) in the dosages that had no obvious cytotoxicity. Using proteomics analysis, we found several osteogenic differentiation-related proteins associated with the effect of crenigacestat on VICs differentiation. Taking into account that crenigacestat is FDA approved for clinical trials for anti-tumor therapy, we argue that this drug could be considered as a potential inhibitor of cardiovascular calcification.

show abstract

Section: Discussionmentioning

confidence: 99%

Crenigacestat (LY3039478) inhibits osteogenic differentiation of human valve interstitial cells from patients with aortic valve calcification in vitro

Lobov

Boyarskaya²,

Kachanova³

et al. 2022

Front. Cardiovasc. Med.

View full text Add to dashboard Cite

show abstract

“…The nuances of the association between lipoprotein complexes and calcific AS are discussed in detail by Rogers and Aikawa6 who suggest that ‘Clinical studies assessing the effectiveness of Lp(a) or ApoCIII antisense oligonucleotides, EO6 antibodies or other means of targeting these apolipoproteins and oxidised lipids could be the next major therapeutic step to identify non-surgical interventions for calcific aortic valve disease, particularly in the high-risk population of patients with elevated Lp(a).’(figure 4)…”

mentioning

confidence: 99%

Heartbeat: bathing daily is associated with a lower cardiovascular risk

Otto

2020

Heart

View full text Add to dashboard Cite

Dissecting Calcific Aortic Valve Disease—The Role, Etiology, and Drivers of Valvular Fibrosis

Büttner

Feistner

Lurz

et al. 2021

Front. Cardiovasc. Med.

View full text Add to dashboard Cite

Calcific aortic valve disease (CAVD) is a highly prevalent and progressive disorder that ultimately causes gradual narrowing of the left ventricular outflow orifice with ensuing devastating hemodynamic effects on the heart. Calcific mineral accumulation is the hallmark pathology defining this process; however, fibrotic extracellular matrix (ECM) remodeling that leads to extensive deposition of fibrous connective tissue and distortion of the valvular microarchitecture similarly has major biomechanical and functional consequences for heart valve function. Significant advances have been made to unravel the complex mechanisms that govern these active, cell-mediated processes, yet the interplay between fibrosis and calcification and the individual contribution to progressive extracellular matrix stiffening require further clarification. Specifically, we discuss (1) the valvular biomechanics and layered ECM composition, (2) patterns in the cellular contribution, temporal onset, and risk factors for valvular fibrosis, (3) imaging valvular fibrosis, (4) biomechanical implications of valvular fibrosis, and (5) molecular mechanisms promoting fibrotic tissue remodeling and the possibility of reverse remodeling. This review explores our current understanding of the cellular and molecular drivers of fibrogenesis and the pathophysiological role of fibrosis in CAVD.

show abstract

Complex association of lipoprotein(a) with aortic stenosis

Cited by 3 publications

References 10 publications

Crenigacestat (LY3039478) inhibits osteogenic differentiation of human valve interstitial cells from patients with aortic valve calcification in vitro

Crenigacestat (LY3039478) inhibits osteogenic differentiation of human valve interstitial cells from patients with aortic valve calcification in vitro

Heartbeat: bathing daily is associated with a lower cardiovascular risk

Dissecting Calcific Aortic Valve Disease—The Role, Etiology, and Drivers of Valvular Fibrosis

Contact Info

Product

Resources

About