Advances in Pathophysiology of Calcific Aortic Valve Disease Propose Novel Molecular Therapeutic Targets

Hulin, Alexia; Hego, Alexandre; Lancellotti, Patrizio; Oury, Cécile

doi:10.3389/fcvm.2018.00021

Cited by 51 publications

(59 citation statements)

References 106 publications

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“…AVICs are the predominant cells in aortic valve leaflets and play an important role in maintaining valvular homeostasis. In the pathological condition of CAVD, however, AVICs synthesize and secret ECM proteins, cytokines and growth factors and thus become key cells involved in valvular inflammation [42]. However, the mechanism by which AVICs adapt a proinflammatory phenotype remains unclear [43].…”

Section: Discussionmentioning

confidence: 99%

Mechanistic Roles of Matrilin-2 and Klotho in Modulating the Inflammatory Activity of Human Aortic Valve Cells

Yao

Zhang

Zhai

et al. 2020

Cells

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Background: Calcific aortic valve disease (CAVD) is a chronic inflammatory disease. Soluble extracellular matrix (ECM) proteins can act as damage-associated molecular patterns and may induce valvular inflammation. Matrilin-2 is an ECM protein and has been found to elevate the pro-osteogenic activity in human aortic valve interstitial cells (AVICs). Klotho, an anti-aging protein, appears to have anti-inflammatory properties. The effect of matrilin-2 and Klotho on AVIC inflammatory responses remains unclear. Methods and Results: Isolated human AVICs were exposed to matrilin-2. Soluble matrilin-2 induced the production of ICAM-1, MCP-1, and IL-6. It also induced protein kinase R (PKR) activation via Toll-like receptor (TLR) 2 and 4. Pretreatment with PKR inhibitors inhibited NF-κB activation and inflammatory mediator production induced by matrilin-2. Further, recombinant Klotho suppressed PKR and NF-κB activation and markedly reduced the production of inflammatory mediators in human AVICs exposed to matrilin-2. Conclusions: This study revealed that soluble matrilin-2 upregulates AVIC inflammatory activity via activation of the TLR-PKR-NF-κB pathway and that Klotho is potent to suppress AVIC inflammatory responses to a soluble ECM protein through inhibiting PKR. These novel findings indicate that soluble matrilin-2 may accelerate the progression of CAVD by inducing valvular inflammation and that Klotho has the potential to suppress valvular inflammation.

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Section: Discussionmentioning

confidence: 99%

Mechanistic Roles of Matrilin-2 and Klotho in Modulating the Inflammatory Activity of Human Aortic Valve Cells

Yao

Zhang

Zhai

et al. 2020

Cells

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“…Согласно мнению западных исследователей, в большинстве случаев развитие КБАК у взрослых являлось результатом идиопатической кальцификации и дистрофических изменений нормального клапана, либо было следствием ревматического поражения клапана, либо кальцификации и фиброза врожденного двустворчатого АК [6]. В 90-х годах было доказано, что клапанный кальциноз представляет собой активный патологический процесс, включающий хроническое воспаление, липидную инфильтрацию [7], образование кальциевых депозитов, активацию ренин-ангиотензиновой системы [8]. В наши дни не теряют своей актуальности все приведенные выше теории формирования КБАК.…”

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Cellular and molecular mechanisms of calcific aortic valve disease

Vanuyto E¹,

Байкулова

Боева³

2019

Russ J Cardiol

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The review provides current data on the pathogenesis of calcific aortic valve disease (CAVD) — a widespread disease with unfavorable prognosis. Currently, there are no effective therapeutic methods for the prevention and treatment of this pathology with the exception of valve replacement surgery. The role of genetic and hereditary factors in the occurrence of CAVD is considered, the leading pathogenetic mechanisms are described taking into account the stage of the disease. In particular, in the initiation phase of calcification, deposition of oxidized lipoproteins in the cusps and local inflammation plays the leading role. In the progression phase, active ectopic calcification dominates, similar to the process of bone formation. The study of the pathogenesis of CAVD seems appropriate taking into account the prospect of developing new effective therapeutic and prophylactic approaches.

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“…In histological materials, it can be found that the superoxide in the stenotic valves is around the calcification zones. The key role in the development of aortic valve stenosis is played by "uncoupled" NOS and not by NADPH; see Figure 1 Inflammatory cytokines, TNF-a and IL-6 reduce the release of NOS (Hulin et al, 2018). TNF-a causes loss of the protective function of the valvular interstitial cells, chronic inflammation, and osteogenic activation by reducing SOD and tetrahydrobiopterin (BH4) (Farrar et al, 2015).…”

Section: Matrix Metalloproteinases (Mmp) and Tissue Inhibitors Of Metmentioning

confidence: 99%

Inflammatory and Non-Inflammatory Risk Factors in Acquired Aortic Valve Stenosis. Doctoral Thesis

Hofmanis¹

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ANNOTATIONCalcific stenosis of the aortic valve (AVS) manifests with fibro-calcific remodelation (transformation) of the aortic valve (AV), which is a slow process of chronic inflammation and calcification with completely unexplored and ambiguous etiology and pathogenesis.Currently, there is no medical treatment to stop or delay the progression of the disease.The only treatment available is a surgical replacement of AV or transcathether aortic valve implantation. With increasing people's survival the number of patients with clinically relevant AVS is increasing.Almost in 25% of people after the age of 65 echocardiographically AV sclerosis is found and about 17% of these people further develop AVS. The time between diagnosis of AV sclerosis and development of severe AVS is on average 6-8 years.The aim of the research work is to analyze and find out which factors involved in the inflammation and calcification process, cell-produced regulatory molecules (cytokines) affect AVS development in all three AVS severity degrees and to what extent. As a result, some biomarkers could be isolated to predict the rate of progression of AVS. Cell-produced regulatory molecules (cytokines) were detected in blood serum and plasma (thioredoxin reductase-1, mieloperoxidase).The interaction of oxidative stress and inflammation in all three AVS severity degrees was analyzed during the research work. The direct and indirect effects of total cholesterol and its fractions on the development of AVS were also re-evaluated.The conducted clinical-analytical study is a prospective case-control study of mixed type. 102 patients were selected voluntarily according to inclusion and exclusion criteria and divided into two basic groups: the control group and the AVS group. Individuals in the control group were included according to an echocardiographically approved healthy aortic valve between the age of 50 to 80 years, which corresponds to the AVS patients' age at the 2012 European Society of Cardiology and the European Association for Cardio-Thoracic Surgery Guidelines for the management of valvular heart disease. Patients of the AVS group were divided into three subgroups according to the degree of the AV stenosis, based on the 2012 European Society of Cardiology and the European Association for Cardio-Thoracic Surgery Guidelines for the Management of Valvular Heart Disease.In the study for the first time in the Latvia population, inflammatory and noninflammatory factors, cell-produced regulatory molecules (cytokines) in blood serum and plasma were analyzed. The obtained results were compared between the control group and all three AVS grades. 3 Knowing recent studies on etiopathogenesis of the calcific AVS, inflammatory and noninflammatory factors (chemerin, FGF-21, TrxR1 and MPO) that have not been studied in AVS patients so far were identified.The obtained results provide more complete information on the pathogenesis of AVS and the correlation between the analyzed inflammatory and non-inflammatory factors. The relationship between chemerin...

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Advances in Pathophysiology of Calcific Aortic Valve Disease Propose Novel Molecular Therapeutic Targets

Cited by 51 publications

References 106 publications

Mechanistic Roles of Matrilin-2 and Klotho in Modulating the Inflammatory Activity of Human Aortic Valve Cells

Mechanistic Roles of Matrilin-2 and Klotho in Modulating the Inflammatory Activity of Human Aortic Valve Cells

Cellular and molecular mechanisms of calcific aortic valve disease

Inflammatory and Non-Inflammatory Risk Factors in Acquired Aortic Valve Stenosis. Doctoral Thesis

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