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Molecular Mechanisms of Aortic Valve Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 9134

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Special Issue Editor

Dr. Philip M. Coan

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Guest Editor

Imperial College London, London, UK
Interests: gene-targeting; functional genomics; aortic stenosis; cardiovascular disease; metabolic syndrome; fetal/placental programming

Special Issue Information

Dear Colleagues,

Aortic valve stenosis is an increasingly prevalent heart disease due to an aging population. No treatment options are available that delay or reverse progression of this disease, making it a major unmet clinical need. The historical research focus on hypertension, atherosclerosis, and coronary heart disease, together with the previous paradigm that aortic valve stenosis was a passive process, have meant that there is much to be understood about the causal molecular mechanisms underlying the development and progression of the active disease process which underpins aortic valve stenosis, fibrosis, and calcification. In this Special Issue, we aim to host a collection of novel research insights from in vivo, ex vivo, and in vitro studies on the disease mechanisms involved that may provide the basis for much needed therapeutic options for aortic valve stenosis.

Dr. Philip M. Coan
Guest Editor

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Keywords

Aortic valve
Stenosis
Calcification
Fibrosis
Mechanisms

Published Papers (4 papers)

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Research

13 pages, 4705 KiB

Open AccessArticle

PPAR-Gamma Activation May Inhibit the In Vivo Degeneration of Bioprosthetic Aortic and Aortic Valve Grafts under Diabetic Conditions

by Shintaro Katahira, Yukiharu Sugimura, Sophia Grupp, Robin Doepp, Jessica Isabel Selig, Mareike Barth, Artur Lichtenberg and Payam Akhyari

Int. J. Mol. Sci. 2021, 22(20), 11081; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011081 - 14 Oct 2021

Cited by 1 | Viewed by 1434

Abstract

Background: We aimed to examine the anti-calcification and anti-inflammatory effects of pioglitazone as a PPAR-gamma agonist on bioprosthetic-valve-bearing aortic grafts in a rat model of diabetes mellitus (DM). Methods: DM was induced in male Wistar rats by high-fat diet with an intraperitoneal streptozotocin (STZ) injection. The experimental group received additional pioglitazone, and controls received normal chow without STZ (n = 20 each group). Cryopreserved aortic donor grafts including the aortic valve were analyzed after 4 weeks and 12 weeks in vivo for analysis of calcific bioprosthetic degeneration. Results: DM led to a significant media proliferation at 4 weeks. The additional administration of pioglitazone significantly increased circulating adiponectin levels and significantly reduced media thickness at 4 and 12 weeks, respectively (p = 0.0002 and p = 0.0107, respectively). Graft media calcification was highly significantly inhibited by pioglitazone after 12 weeks (p = 0.0079). Gene-expression analysis revealed a significant reduction in relevant chondro-osteogenic markers osteopontin and RUNX-2 by pioglitazone at 4 weeks. Conclusions: Under diabetic conditions, pioglitazone leads to elevated circulating levels of adiponectin and to an inhibition of bioprosthetic graft degeneration, including lower expression of chondro-osteogenic genes, decreased media proliferation, and inhibited graft calcification in a small-animal model of DM. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Aortic Valve Disease)

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20 pages, 2371 KiB

Open AccessArticle

Interferons Are Pro-Inflammatory Cytokines in Sheared-Stressed Human Aortic Valve Endothelial Cells

by Iván Parra-Izquierdo, Tania Sánchez-Bayuela, Javier López, Cristina Gómez, Enrique Pérez-Riesgo, J. Alberto San Román, Mariano Sánchez Crespo, Magdi Yacoub, Adrian H. Chester and Carmen García-Rodríguez

Int. J. Mol. Sci. 2021, 22(19), 10605; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910605 - 30 Sep 2021

Cited by 8 | Viewed by 2220

Abstract

Calcific aortic valve disease (CAVD) is an athero-inflammatory process. Growing evidence supports the inflammation-driven calcification model, mediated by cytokines such as interferons (IFNs) and tumor necrosis factor (TNF)-α. Our goal was investigating IFNs’ effects in human aortic valve endothelial cells (VEC) and the potential differences between aortic (aVEC) and ventricular (vVEC) side cells. The endothelial phenotype was analyzed by Western blot, qPCR, ELISA, monocyte adhesion, and migration assays. In mixed VEC populations, IFNs promoted the activation of signal transducers and activators of transcription-1 and nuclear factor-κB, and the subsequent up-regulation of pro-inflammatory molecules. Side-specific VEC were activated with IFN-γ and TNF-α in an orbital shaker flow system. TNF-α, but not IFN-γ, induced hypoxia-inducible factor (HIF)-1α stabilization or endothelial nitric oxide synthase downregulation. Additionally, IFN-γ inhibited TNF-α–induced migration of aVEC. Also, IFN-γ triggered cytokine secretion and adhesion molecule expression in aVEC and vVEC. Finally, aVEC were more prone to cytokine-mediated monocyte adhesion under multiaxial flow conditions as compared with uniaxial flow. In conclusion, IFNs promote inflammation and reduce TNF-α–mediated migration in human VEC. Moreover, monocyte adhesion was higher in inflamed aVEC sheared under multiaxial flow, which may be relevant to understanding the initial stages of CAVD. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Aortic Valve Disease)

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24 pages, 6067 KiB

Open AccessArticle

Crosstalk of Diabetic Conditions with Static Versus Dynamic Flow Environment—Impact on Aortic Valve Remodeling

by Jessica I. Selig, Joana Boulgaropoulos, Naima Niazy, D. Margriet Ouwens, Karlheinz Preuß, Patrick Horn, Ralf Westenfeld, Artur Lichtenberg, Payam Akhyari and Mareike Barth

Int. J. Mol. Sci. 2021, 22(13), 6976; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22136976 - 28 Jun 2021

Cited by 3 | Viewed by 1833

Abstract

Type 2 diabetes mellitus (T2D) is one of the prominent risk factors for the development and progression of calcific aortic valve disease. Nevertheless, little is known about molecular mechanisms of how T2D affects aortic valve (AV) remodeling. In this study, the influence of hyperinsulinemia and hyperglycemia on degenerative processes in valvular tissue is analyzed in intact AV exposed to an either static or dynamic 3D environment, respectively. The complex native dynamic environment of AV is simulated using a software-governed bioreactor system with controlled pulsatile flow. Dynamic cultivation resulted in significantly stronger fibrosis in AV tissue compared to static cultivation, while hyperinsulinemia and hyperglycemia had no impact on fibrosis. The expression of key differentiation markers and proteoglycans were altered by diabetic conditions in an environment-dependent manner. Furthermore, hyperinsulinemia and hyperglycemia affect insulin-signaling pathways. Western blot analysis showed increased phosphorylation level of protein kinase B (AKT) after acute insulin stimulation, which was lost in AV under hyperinsulinemia, indicating acquired insulin resistance of the AV tissue in response to elevated insulin levels. These data underline a complex interplay of diabetic conditions on one hand and biomechanical 3D environment on the other hand that possesses an impact on AV tissue remodeling. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Aortic Valve Disease)

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18 pages, 3146 KiB

Open AccessArticle

Metabolomics in Severe Aortic Stenosis Reveals Intermediates of Nitric Oxide Synthesis as Most Distinctive Markers

by Beau Olivier van Driel, Maike Schuldt, Sila Algül, Evgeni Levin, Ahmet Güclü, Tjeerd Germans, Albert C. van Rossum, Jiayi Pei, Magdalena Harakalova, Annette Baas, Judith J. M. Jans and Jolanda van der Velden

Int. J. Mol. Sci. 2021, 22(7), 3569; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073569 - 30 Mar 2021

Cited by 13 | Viewed by 3106

Abstract

Background: Calcific aortic valve disease (CAVD) is a rapidly growing global health problem with an estimated 12.6 million cases globally in 2017 and a 112% increase of deaths since 1990 due to aging and population growth. CAVD may develop into aortic stenosis (AS) by progressive narrowing of the aortic valve. AS is underdiagnosed, and if treatment by aortic valve replacement (AVR) is delayed, this leads to poor recovery of cardiac function, absence of symptomatic improvement and marked increase of mortality. Considering the current limitations to define the stage of AS-induced cardiac remodeling, there is need for a novel method to aid in the diagnosis of AS and timing of intervention, which may be found in metabolomics profiling of patients. Methods: Serum samples of nine healthy controls and 10 AS patients before and after AVR were analyzed by untargeted mass spectrometry. Multivariate modeling was performed to determine a metabolic profile of 30 serum metabolites which distinguishes AS patients from controls. Human cardiac microvascular endothelial cells (CMECs) were incubated with serum of the AS patients and then stained for ICAM-1 with Western Blot to analyze the effect of AS patient serum on endothelial cell activation. Results: The top 30 metabolic profile strongly distinguishes AS patients from healthy controls and includes 17 metabolites related to nitric oxide metabolism and 12 metabolites related to inflammation, in line with the known pathomechanism for calcific aortic valve disease. Nine metabolites correlate strongly with left ventricular mass, of which three show reversal back to control values after AVR. Western blot analysis of CMECs incubated with AS patient sera shows a significant reduction (14%) in ICAM-1 in AS samples taken after AVR compared to AS patient sera before AVR. Conclusion: Our study defined a top 30 metabolic profile with biological and clinical relevance, which may be used as blood biomarker to identify AS patients in need of cardiac surgery. Future studies are warranted in patients with mild-to-moderate AS to determine if these metabolites reflect disease severity and can be used to identify AS patients in need of cardiac surgery. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Aortic Valve Disease)

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