ArticleCardiovascular pathology : the official journal of the Society for Cardiovascular Pathology
Smad2-dependent glycosaminoglycan elongation in aortic valve interstitial cells enhances binding of LDL to proteoglycans.
Article in Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 28 citations in OpenAlex.
- Deciphering the Enigma of Calcific Aortic Valve Disease: The Pivotal Role of Animal Models in Unraveling Pathogenesis and Advancing Therapeutic Strategies.Biomedicines · 2025Review
- Article
- Hypoxia Stimulates Synthesis of Neutrophil Gelatinase-Associated Lipocalin in Aortic Valve Disease.Frontiers in cardiovascular medicine · 2019Article
- Advances in Pathophysiology of Calcific Aortic Valve Disease Propose Novel Molecular Therapeutic Targets.Frontiers in cardiovascular medicine · 2018Article
- Dysregulation of hyaluronan homeostasis during aortic valve disease.Matrix biology : journal of the International Society for Matrix Biology · 2017Article
- Valve Interstitial Cells: The Key to Understanding the Pathophysiology of Heart Valve Calcification.Journal of the American Heart Association · 2017Review
- Calcific aortic stenosis.Nature reviews. Disease primers · 2016Review
- Innate and Adaptive Immunity in Calcific Aortic Valve Disease.Journal of immunology research · 2015Review
- Defining the role of fluid shear stress in the expression of early signaling markers for calcific aortic valve disease.PloS one · 2013Article
- Macrophages bind LDL using heparan sulfate and the perlecan protein core.The Journal of biological chemistryArticle
- Extracellular Matrix Dynamics in Aortic Valve Health and Disease: Insights into Fibrocalcific Remodeling and Creation of Biomimetic Platforms.Journal of the Heart Valve SocietyArticle
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Authors and funding
7 authors at 6 institutions in 2 countries.
Funding
Abstract
objectiveCalcific aortic valve disease is a progressive condition that shares some common pathogenic features with atherosclerosis. Transforming growth factor-β1 is a recognized mediator of atherosclerosis and is expressed in aortic valve lesions. Transforming growth factorβ1 stimulates glycosaminoglycan elongation of proteoglycans that is associated with increased lipid binding. We investigated the presence of transforming growth factor-β1 and downstream signaling intermediates in diseased human aortic valves and the effects of activated transforming growth factor-β1 receptor signaling on aortic valve interstitial cell proteoglycan synthesis and lipid binding as a possible mechanism for the initiation of the early lesion of calcific aortic valve disease. METHODS AND
resultsDiseased human aortic valve leaflets demonstrated strong immunohistochemical staining for transforming growth factor-β1 and phosphorylated Smad2/3. In primary porcine aortic valve interstitial cells, Western blots showed that transforming growth factor-β1 stimulated phosphorylation in both the carboxy and linker regions of Smad2/3, which was inhibited by the transforming growth factor-β1 receptor inhibitor SB431542. Gel electrophoresis and size exclusion chromatography demonstrated that SB431542 decreased transforming growth factor-β1-mediated [(35)S]-sulfate incorporation into proteoglycans in a dose-dependent manner. Further, in proteoglycans derived from transforming growth factor-β1-treated valve interstitial cells, gel mobility shift assays demonstrated that inhibition of transforming growth factor-β1 receptor signaling resulted in decreased lipid binding.
conclusionsClassic transforming growth factor-β1 signaling is present in human aortic valves in vivo and contributes to the modification of proteoglycans expressed by valve interstitial cells in vitro. These findings suggest that transforming growth factor-β1 may promote increased low-density lipoprotein binding in the early phases of calcific aortic valve disease.
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