Autotaxin inhibition attenuates the aortic valve calcification by suppressing inflammation-driven fibro-calcific remodeling of valvular interstitial cells (vol 22, pg 122, 2024)

被引：0

作者：

Yoon, Dohee ^{[1
,2
]}

Choi, Bongkun ^{[1
,2
]}

Kim, Ji-Eun ^{[1
,2
]}

Kim, Eun-Young ^{[1
,2
]}

Chung, Soo-Hyun ^{[1
,2
]}

Min, Hyo-Jin ^{[1
,2
]}

Sung, Yoolim ^{[1
,2
]}

Chang, Eun-Ju ^{[1
,2
]}

Song, Jae-Kwan ^{[3
]}

机构：

[1] Univ Ulsan, Asan Med Ctr, Dept Biochem & Mol Biol, Brain Korea Project 21,Coll Med, 88 Olymp Ro 43 Gil, Seoul 05505, South Korea

[2] Univ Ulsan, Stem Cell Immunomodulat Res Ctr, Asan Med Ctr, Coll Med, 88 Olymp Ro 43 Gil, Seoul 05505, South Korea

[3] Univ Ulsan, Asan Med Ctr, Dept Internal Med, Div Cardiol,Coll Med, 88 Olymp Ro 43 Gil, Seoul 05505, South Korea

来源：

BMC MEDICINE | 2024年 / 22卷 / 01期

基金：

新加坡国家研究基金会;

关键词：

Aortic valve; Autotaxin; Calcification; Fibro-calcific aortic valve disease; Fibrosis;

D O I：

10.1186/s12916-024-03403-1

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BackgroundPatients with fibro-calcific aortic valve disease (FCAVD) have lipid depositions in their aortic valve that engender a proinflammatory impetus toward fibrosis and calcification and ultimately valve leaflet stenosis. Although the lipoprotein(a)-autotaxin (ATX)-lysophosphatidic acid axis has been suggested as a potential therapeutic target to prevent the development of FCAVD, supportive evidence using ATX inhibitors is lacking. We here evaluated the therapeutic potency of an ATX inhibitor to attenuate valvular calcification in the FCAVD animal models.MethodsATX level and activity in healthy participants and patients with FCAVD were analyzed using a bioinformatics approach using the Gene Expression Omnibus datasets, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, and western blotting. To evaluate the efficacy of ATX inhibitor, interleukin-1 receptor antagonist-deficient (Il1rn-/-) mice and cholesterol-enriched diet-induced rabbits were used as the FCAVD models, and primary human valvular interstitial cells (VICs) from patients with calcification were employed.ResultsThe global gene expression profiles of the aortic valve tissue of patients with severe FCAVD demonstrated that ATX gene expression was significantly upregulated and correlated with lipid retention (r = 0.96) or fibro-calcific remodeling-related genes (r = 0.77) in comparison to age-matched non-FCAVD controls. Orally available ATX inhibitor, BBT-877, markedly ameliorated the osteogenic differentiation and further mineralization of primary human VICs in vitro. Additionally, ATX inhibition significantly attenuated fibrosis-related factors' production, with a detectable reduction of osteogenesis-related factors, in human VICs. Mechanistically, ATX inhibitor prohibited fibrotic changes in human VICs via both canonical and non-canonical TGF-beta signaling, and subsequent induction of CTGF, a key factor in tissue fibrosis. In the in vivo FCAVD model system, ATX inhibitor exposure markedly reduced calcific lesion formation in interleukin-1 receptor antagonist-deficient mice (Il1rn-/-, P = 0.0210). This inhibition ameliorated the rate of change in the aortic valve area (P = 0.0287) and mean pressure gradient (P = 0.0249) in the FCAVD rabbit model. Moreover, transaortic maximal velocity (Vmax) was diminished with ATX inhibitor administration (mean Vmax = 1.082) compared to vehicle control (mean Vmax = 1.508, P = 0.0221). Importantly, ATX inhibitor administration suppressed the effects of a high-cholesterol diet and vitamin D2-driven fibrosis, in association with a reduction in macrophage infiltration and calcific deposition, in the aortic valves of this rabbit model.ConclusionsATX inhibition attenuates the development of FCAVD while protecting against fibrosis and calcification in VICs, suggesting the potential of using ATX inhibitors to treat FCAVD.

引用

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