Role of Wnt/β-catenin signaling pathway in the mechanism of calcification of aortic valve

Gu, G.; Chen, Tao; Zhou, Hongmin; Sun, Kexiong; Li, Jun

doi:10.1007/s11596-014-1228-x

Cited by 19 publications

(14 citation statements)

References 10 publications

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“…Normally, NOTCH1 signaling prevents calcification through suppression of master osteoblast transcription factor runt-related transcription factor 2 (RUNX2) whereas loss-of-function mutations in NOTCH1 result in upregulation of BMP2 [55][56][57][58][59]. In addition, activation of glycogen synthase kinase-3 (GSK-3β) and β-catenin in the Wnt/β-catenin signaling pathway also results in osteogenic differentiation of VICs via increased production of ALP [60,61]. Interestingly, methylation of NOTCH1 at the promotor side decreases NOTCH1 expression while the Wnt/β-catenin is being activated leading to transcription of the osteogenic genes RUNX2, SOX9, and BMP2 suggesting an interplay between the NOTCH1 and Wnt/β-catenin pathway [62].…”

Section: The Notch and Wnt-mediated Calcific Regulatory Pathwaysmentioning

confidence: 99%

Lipoprotein(a) as Orchestrator of Calcific Aortic Valve Stenosis

et al. 2019

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Aortic valve stenosis (AVS) is the most prevalent valvular heart disease in the Western World with exponentially increased incidence with age. If left untreated, the yearly mortality rates increase up to 25%. Currently, no effective pharmacological interventions have been established to treat or prevent AVS. The only treatment modality so far is surgical or transcatheter aortic valve replacement (AVR). Lipoprotein(a) [Lp(a)] has been implicated as a pivotal player in the pathophysiology of calcification of the valves. Patients with elevated levels of Lp(a) have a higher risk of hospitalization or mortality due to the presence of AVS. Multiple studies indicated Lp(a) as a likely causal and independent risk factor for AVS. This review discusses the most important findings and mechanisms related to Lp(a) and AVS in detail. During the progression of AVS, Lp(a) enters the aortic valve tissue at damaged sites of the valves. Subsequently, autotaxin converts lysophosphatidylcholine in lysophosphatidic acid (LysoPA) which in turn acts as a ligand for the LysoPA receptor. This triggers a nuclear factor-κB cascade leading to increased transcripts of interleukin 6, bone morphogenetic protein 2, and runt-related transcription factor 2. This progresses to the actual calcification of the valves through production of alkaline phosphatase and calcium depositions. Furthermore, this review briefly mentions potentially interesting therapies that may play a role in the treatment or prevention of AVS in the near future.

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Section: The Notch and Wnt-mediated Calcific Regulatory Pathwaysmentioning

confidence: 99%

Lipoprotein(a) as Orchestrator of Calcific Aortic Valve Stenosis

et al. 2019

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“…In addition, high serum levels of the Wnt antagonists secreted frizzled related protein-3 (sFRP-3), dickkopf-1 (DKK-1), and Wnt inhibitory factor-1 (WIF-1) were identified in patients with symptomatic aortic stenosis in contrast to healthy controls, and the circulating levels of WIF-1 and DKK-1 were found to be predictive of mortality [33]. The differentiation of porcine valve interstitial cells into osteoblast-like cells, a process involved in the calcification of the aortic valve, was found to significantly increase the expression of GSK-3β and β-catenin [34]. …”

Section: Wnt Signaling In Cardiac Repair and Diseasementioning

confidence: 99%

The role of Wnt regulation in heart development, cardiac repair and disease: A tissue engineering perspective

Pahnke

Conant

Huyer

et al. 2016

Biochemical and Biophysical Research Communications

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Wingless-related integration site (Wnt) signaling has proven to be a fundamental mechanism in cardiovascular development as well as disease. Understanding its particular role in heart formation has helped to develop pluripotent stem cell differentiation protocols that produce relatively pure cardiomyocyte populations. The resultant cardiomyocytes have been used to generate heart tissue for pharmaceutical testing, and to study physiological and disease states. Such protocols in combination with induced pluripotent stem cell technology have yielded patient-derived cardiomyocytes that exhibit some of the hallmarks of cardiovascular disease and are therefore being used to model disease states. While FDA approval of new treatments typically requires animal experiments, the burgeoning field of tissue engineering could act as a replacement. This would necessitate the generation of reproducible three-dimensional cardiac tissues in a well-controlled environment, which exhibit native heart properties, such as cellular density, composition, extracellular matrix composition, and structure-function. Such tissues could also enable the further study of Wnt signaling. Furthermore, as Wnt signaling has been found to have a mechanistic role in cardiac pathophysiology, e.g. heart attack, hypertrophy, atherosclerosis, and aortic stenosis, its strategic manipulation could provide a means of generating reproducible and specific, physiological and pathological cardiac models.

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“…The Wnt/β-catenin pathway, in particular, is considered relevant for osteoblastic differentiation for CAVD at the molecular level [13–16], as western blotting and RT-PCR analyses have confirmed the upregulation of β-catenin in calcified aortic valves and in bone in the stenotic aortic valve [17]. Oxidized low density lipoprotein leads to AV calcification in vitro and in vivo and LRP5/Wnt signal and β-catenin are related with cardiovascular calcification [14, 15, 17–19]. The myofibroblastic differentiation processes of VICs have also been related to the Wnt/β-catenin signalling that depends on matrix stiffness and TGF-β1 [20].…”

Section: Introductionmentioning

confidence: 99%

“…The myofibroblastic differentiation processes of VICs have also been related to the Wnt/β-catenin signalling that depends on matrix stiffness and TGF-β1 [20]. Stimulation of porcine VICs by oxidised low density lipoprotein also induces β-catenin expression, leading to the conclusion that Wnt/β-catenin signalling plays a key role in osteoblastic VIC differentiation, thereby contributing to CAVD [14]. Similar results were published by Gao et al, who demonstrated an involvement of the Wnt/β-catenin signalling pathway in osteoblastic VIC differentiation monitored by western blotting and/or RT-PCR detection of extracellular matrix proteins and respective gene markers [21].…”

Section: Introductionmentioning

confidence: 99%

Treatment with XAV-939 prevents in vitro calcification of human valvular interstitial cells

et al. 2018

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The development of a substance or inhibitor-based treatment strategy for the prevention of aortic valve stenosis is a challenge and a main focus of medical research in this area. One strategy may be to use the tankyrase inhibitor XAV-939, which leads to Axin stabilisation and subsequent destruction of the β-catenin complex and dephosphorylation of β-catenin. The dephosphorylated active form of β-catenin (non-phospho-β-catenin) then promotes nuclear transcription that leads to osteogenesis. The aims of the present study were to develop an experimental system for inducing in vitro calcification of human aortic valvular interstitial cells (VICs) to investigate the potential anti-calcific effect of XAV-939 and to analyse expression of the Wnt signalling proteins and Sox9, a chondrogenesis regulator, in this model. Calcification of human VIC cultures was induced by cultivation in an osteogenic medium and the effect of co-incubation with 1μM XAV-939 was monitored. Calcification was quantified when mineral deposits were visible in culture and was histologically verified by von Kossa or Alizarin red staining and by IR-spectroscopy. Protein expression of alkaline phosphatase, Axin, β-catenin and Sox9 were quantified by western blotting. In 58% of the VIC preparations, calcification was induced in an osteogenic culture medium and was accompanied by upregulation of alkaline phosphatase. The calcification induction was prevented by the XAV-939 co-treatment and the alkaline phosphatase upregulation was suppressed. As expected, Axin was upregulated, but the levels of active non-phospho-β-catenin were also enhanced. Sox9 was induced during XAV-939 treatment but apparently not as a result of downregulation of β-catenin signalling. XAV-939 was therefore able to prevent calcification of human VIC cultures, and XAV-939 treatment was accompanied by upregulation of active non-phospho-β-catenin. Although XAV-939 does not downregulate active β-catenin, treatment with XAV-939 results in Sox9 upregulation that may prevent the calcification process.

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Role of Wnt/β-catenin signaling pathway in the mechanism of calcification of aortic valve

Cited by 19 publications

References 10 publications

Lipoprotein(a) as Orchestrator of Calcific Aortic Valve Stenosis

Lipoprotein(a) as Orchestrator of Calcific Aortic Valve Stenosis

The role of Wnt regulation in heart development, cardiac repair and disease: A tissue engineering perspective

Treatment with XAV-939 prevents in vitro calcification of human valvular interstitial cells

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