The Effects of Cell Contraction and Loss of Adhesion on the Apoptosis of Valve Interstitial Cells

2010 ◽  
Author(s):  
Ruogang Zhao ◽  
Lina Lin ◽  
Craig A. Simmons
Keyword(s):  
Shape Change ◽  
Cell Aggregation ◽  
Cell Types ◽  
Interstitial Cells ◽  
Adherent Cell ◽  
Dystrophic Calcification ◽  
Mechanical Stimuli ◽  
Cell Contraction ◽  
Valve Interstitial Cells ◽  
Cytoskeletal Network

Dystrophic calcification in sclerotic aortic valves is associated with apoptosis of myofibroblasts that differentiate from valve interstitial cells (VICs). The factors that regulate apoptosis in sclerotic valves are not known, but may include mechanical stimuli, as is the case in other fibrotic tissues. In support of this hypothesis, we have observed that VICs on stiff collagen matrices that simulate fibrotic tissue differentiate to myofibroblasts and form calcified aggregates that contain apoptotic cells [1]. However, the mechanisms by which cell aggregation leads to VIC apoptosis are unknown. In other cell types, cell contraction caused by release of matrix tension can induce cell apoptosis, but the mechanical transduction pathway regulating this process is unknown [2]. Similarly, cell rounding caused by disrupting the cytoskeletal network has been found to induce apoptosis [3], indicating the cytoskeletal network may play an important role in the cell shape-change related apoptosis pathways. Loss of adhesion between the cell and its matrix is also a well-documented cause for apoptosis of adherent cell types [4].

Characterization of the Elasticity of Valve Interstitial Cells on Soft Substrates Using Atomic Force Microscopy

2012 ◽  
Author(s):  
Haijiao Liu ◽  
Craig A. Simmons ◽  
Yu Sun
Keyword(s):  
Mechanical Properties ◽  
Cell Types ◽  
Interstitial Cells ◽  
Cellular Level ◽  
Mechanical Stimuli ◽  
Valve Interstitial Cells ◽  
Force Microscopy ◽  
Atomic Force ◽  
Sense And Respond

Mechanical stimuli, including the elasticity of the extracellular matrix (ECM), can have profound effects on the function of cells and their responsiveness to other microenvironmental cues, thereby regulating homeostasis and disease development. For example, the response of aortic valve interstitial cells (VICs) to growth factors [1] and VIC differentiation to pathological phenotypes [2] depend on ECM elasticity. The ability of cells to sense and respond to mechanical stimuli depends on several factors, including their inherent cellular-level mechanical properties. The mechanical properties of suspended VICs [3, 4] and VICs grown on stiff glass/polystyrene [5] have been reported. However, neither of these test conditions is physiological, as VICs adhere to ECM that is orders of magnitude more compliant than glass. Some other cell types adapt their stiffness to that of their substrate [6]; we hypothesized that adherent VICs would similarly change their elasticity in response to the elastic properties of their ECM.

Abstract 18216: Epigenetic Up-regulation of α-smooth Muscle Actin Expression and Cell Aggregation in Human Aortic Valve Interstitial Cells Promotes Calcific Nodule Formation

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Rui Song ◽  
David A. Fullerton ◽  
Lihua Ao ◽  
Kesen Zhao ◽  
Xianzhong Meng
Keyword(s):  
Smooth Muscle ◽  
Aortic Valve ◽  
Smooth Muscle Actin ◽  
Cell Aggregation ◽  
Interstitial Cells ◽  
Nodule Formation ◽  
Muscle Actin ◽  
Aortic Valves ◽  
Valve Interstitial Cells ◽  
Tgf Β1

Older people are at risk of calcific aortic valve disease. Aortic valve interstitial cells (AVICs) play an important role in nodular calcification in aortic valve leaflets. AVICs in human aortic valves consist of fibroblasts and myofibroblasts that express α-smooth muscle actin (α-SMA). We have observed that AVICs of diseased aortic valves have greater osteogenic activities. However, molecular mechanism underlying AVIC formation of calcification nodules is not well understood. We hypothesized that an epigenetic mechanism promotes AVIC calcification nodule formation through induction of α-SMA expression and cell aggregation. Methods and Results: MiRNA profiles in AVICs from normal and diseased human aortic valves were analyzed by miRNA array and real-time qPCR. Diseased AVICs displayed higher levels of miR-486. Immunoblotting and immunofluorescence staining revealed that diseased AVICs had higher levels of α-SMA and α-SMA fibers. Inhibition of miR-486 by lentiviral-delivered miR-486 antagomir in diseased AVICs suppressed α-SMA expression and cell aggregation, resulting in reduced calcification nodule formation. Conversely, lentiviral-delivered miR-486 mimic in normal AVICs induced α-SMA expression and cell aggregation, leading to exacerbated calcification nodule formation. Stimulation of normal AVICs with pro-osteogenic mediators TGF-β1 and BMP-2 up-regulated miR-486 levels. MiR-486 antagomir reduced α-SMA expression, cell aggregation and calcification nodule formation in cells exposed to TGF-β1 or BMP-2. Further, miR-486 mimic induced AKT phosphorylation. Inhibition of AKT decreased α-SMA expression and cell aggregation induced by miR-486 mimic in normal AVICs. Knockdown of α-SMA suppressed cell aggregation and calcification nodule formation. Conclusions: The pro-osteogenic phenotype of AVICs of diseased aortic valves is associated with up-regulated levels of miR-486 and α-SMA. MiR-486 modulates the AKT pathway to up-regulate α-SMA expression and cell aggregation that are required for calcification nodule formation. These novel findings indicate that miR-486 contributes to the mechanism underlying aortic valve calcification and appears to be a therapeutic target for suppression of valvular osteogenic activity.

scholarly journals Hypoxia-mediated regulation of the secretory properties of mitral valve interstitial cells

2017 ◽  
Vol 313 (1) ◽  
pp. H14-H23 ◽  
Author(s):  
Kareem Salhiyyah ◽  
Padmini Sarathchandra ◽  
Najma Latif ◽  
Magdi H. Yacoub ◽  
Adrian H. Chester
Keyword(s):  
Extracellular Matrix ◽  
Mitral Valve ◽  
Heart Valve ◽  
Potential Role ◽  
Complex Function ◽  
Interstitial Cells ◽  
Matrix Remodeling ◽  
Mechanical Stimuli ◽  
Valve Interstitial Cells

The sophisticated function of the mitral valve depends to a large extent on its extracellular matrix (ECM) and specific cellular components. These are tightly regulated by a repertoire of mechanical stimuli and biological pathways. One potentially important stimulus is hypoxia. The purpose of this investigation is to determine the effect of hypoxia on the regulation of mitral valve interstitial cells (MVICs) with respect to the synthesis and secretion of extracellular matrix proteins. Hypoxia resulted in reduced production of total collagen and sulfated glycosaminoglycans (sGAG) in cultured porcine MVICs. Increased gene expression of matrix metalloproteinases-1 and -9 and their tissue inhibitors 1 and 2 was also observed after incubation under hypoxic conditions for up to 24 h. Hypoxia had no effect on MVIC viability, morphology, or phenotype. MVICs expressed hypoxia-inducible factor (HIF)-1α under hypoxia. Stimulating HIF-1α chemically caused a reduction in the amount of sGAG produced, similar to the effect observed under hypoxia. Human rheumatic valves had greater expression of HIF-1α compared with normal or myxomatous degenerated valves. In conclusion, hypoxia affects the production of certain ECM proteins and expression of matrix remodeling enzymes by MVICs. The effects of hypoxia appear to correlate with the induction of HIF-1α. This study highlights a potential role of hypoxia and HIF-1α in regulating the mitral valve, which could be important in health and disease. NEW & NOTEWORTHY This study demonstrates that hypoxia regulates extracellular matrix secretion and the remodeling potential of heart valve interstitial cells. Expression of hypoxia-induced factor-1α plays a role in these effects. These data highlight the potential role of hypoxia as a physiological mediator of the complex function of heart valve cells.

Chondrocyte Translocation and Orientation to Applied DC Electric Fields

1999 ◽  
Author(s):  
Robert L. Mauck ◽  
Pen-hsiu G. Chao ◽  
Beth Gilbert ◽  
Wilmot B. Valhmu ◽  
Clark T. Hung
Keyword(s):  
Electric Fields ◽  
Bone Cells ◽  
Shape Change ◽  
Cell Types ◽  
Neural Cells ◽  
Similar Response ◽  
Mechanical Stimuli ◽  
Directed Movement ◽  
Streaming Potentials ◽  
Dc Electric Fields

Abstract Chemical and mechanical stimuli are known to cause directed movement in a number of different cell types. Less prominently studied, direct current (DC) electric fields are known to induce a similar response. In this study, we report on DC electric field-induced chondrocyte migration and re-orientation. Galvanotaxis and galvanotropism, migration and shape change in response to applied DC electric fields, respectively, have been demonstrated in many cells. For instance, field strengths of 1–10 V/cm have been reported to induce migration in keratinocytes. corneal epithelial cells, bone cells, fibroblasts and neural cells [1,7,8,11]. Recently, we have demonstrated for the first time that chondrocytes exhibit a galvanotactic response, realigning and migrating in response to applied DC electric fields (6 V/cm) [6]. In cartilage, chondrocytes may see electric fields associated with streaming potentials estimated to be up to 15 V/cm with current densities of up to 0.1A/cm2 [2]. The aim of this study was to explore basic science aspects of directed cell migration under applied DC electric fields and to investigate the potential application of this phenomena for tissue engineering, healing and repair of cartilage. The ability to direct cell growth and function will have significant implications on the bioengineering of replacement tissues.

scholarly journals Survival-Related Autophagic Activity Versus Procalcific Death in Cultured Aortic Valve Interstitial Cells Treated With Critical Normophosphatemic-Like Phosphate Concentrations

2017 ◽  
Vol 65 (3) ◽  
pp. 125-138 ◽  
Author(s):  
Antonella Bonetti ◽  
Alberto Della Mora ◽  
Magali Contin ◽  
Giorgia Gregoraci ◽  
Franco Tubaro ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Phosphatase Activity ◽  
Interstitial Cells ◽  
Dystrophic Calcification ◽  
Normal Range ◽  
Valve Interstitial Cells ◽  
Proinflammatory Mediators ◽  
Intracellular Release ◽  
Cuprolinic Blue ◽  
Rich Material

Valve dystrophic calcification is a common disorder affecting normophosphatemic subjects. Here, cultured aortic valve interstitial cells (AVICs) were treated 3 to 28 days with phosphate (Pi) concentrations spanning the normal range in humans (0.8, 1.3, and 2.0 mM) alone or supplemented with proinflammatory stimuli to assess possible priming of dystrophic-like calcification. Compared with controls, spectrophotometric analyses revealed marked increases in calcium amounts and alkaline phosphatase activity for 2.0-mM-Pi-containing cultures, with enhancing by proinflammatory mediators. Ultrastructurally, AVICs treated with low/middle Pi concentrations showed an enormous endoplasmic reticulum (ER) enclosing organelle debris, so apparently executing a survival-related atypical macroautophagocytosis, consistently with ultracytochemical demonstration of ER-associated acid phosphatase activity and decreases in autophagosomes and immunodetectable MAP1LC3. In contrast, AVICs cultured at 2.0-mM Pi underwent mineralization due to intracellular release and peripheral layering of phospholipid-rich material acting as hydroxyapatite nucleator, as revealed by Cuprolinic Blue and von Kossa ultracytochemical reactions. Lack of immunoblotted caspase-3 cleaved form indicated apoptosis absence for all cultures. In conclusion, fates of cultured AVICs were crucially driven by Pi concentration, suggesting that serum Pi levels just below the upper limit of normophosphatemia in humans may represent a critical watershed between macroautophagy-associated cell restoring and procalcific cell death.

Establishment of oxidative stress model with human valve interstitial cells mediated by H2O2

2015 ◽  
Vol 36 (1) ◽  
pp. 1
Author(s):  
Pu-xi XIONG ◽  
Lin HAN ◽  
Xiao-hong LIU ◽  
De-jun GONG ◽  
Wei-jun PAN ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Interstitial Cells ◽  
Stress Model ◽  
Valve Interstitial Cells

scholarly journals Heme-Mediated Activation of the Nrf2/HO-1 Axis Attenuates Calcification of Valve Interstitial Cells

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 427
Author(s):  
Enikő Balogh ◽  
Arpan Chowdhury ◽  
Haneen Ababneh ◽  
Dávid Máté Csiki ◽  
Andrea Tóth ◽  
...  
Keyword(s):  
Target Gene ◽  
Interstitial Cells ◽  
Protective Role ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Valvular Interstitial Cells ◽  
Aortic Valves ◽  
Antioxidant Genes ◽  
Valve Interstitial Cells ◽  
Nrf2 Target Gene

Calcific aortic valve stenosis (CAVS) is a heart disease characterized by the progressive fibro-calcific remodeling of the aortic valves, an actively regulated process with the involvement of the reactive oxygen species-mediated differentiation of valvular interstitial cells (VICs) into osteoblast-like cells. Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the expression of a variety of antioxidant genes, and plays a protective role in valve calcification. Heme oxygenase-1 (HO-1), an Nrf2-target gene, is upregulated in human calcified aortic valves. Therefore, we investigated the effect of Nrf2/HO-1 axis in VIC calcification. We induced osteogenic differentiation of human VICs with elevated phosphate and calcium-containing osteogenic medium (OM) in the presence of heme. Heme inhibited Ca deposition and OM-induced increase in alkaline phosphatase and osteocalcin (OCN) expression. Heme induced Nrf2 and HO-1 expression in VICs. Heme lost its anti-calcification potential when we blocked transcriptional activity Nrf2 or enzyme activity of HO-1. The heme catabolism products bilirubin, carbon monoxide, and iron, and also ferritin inhibited OM-induced Ca deposition and OCN expression in VICs. This study suggests that heme-mediated activation of the Nrf2/HO-1 pathway inhibits the calcification of VICs. The anti-calcification effect of heme is attributed to the end products of HO-1-catalyzed heme degradation and ferritin.

3D Contractile Responses of Normal and Diseased Human Aortic Valve Interstitial Cells

2021 ◽  
Vol 5 (sup1) ◽  
pp. 1-1
Author(s):  
Alex Khang ◽  
Chiara Camillo ◽  
Giovanni Ferrari ◽  
Michael S. Sacks
Keyword(s):  
Aortic Valve ◽  
Interstitial Cells ◽  
Contractile Responses ◽  
Valve Interstitial Cells ◽  
Human Aortic Valve

Production and Analysis of High Resolution Polymer Replicas of Fibrillar Collagen

1999 ◽  
Vol 5 (S2) ◽  
pp. 398-399
Author(s):  
P. Sims ◽  
B. Todd ◽  
S. Eppell ◽  
T. Li ◽  
K. Park ◽  
...  
Keyword(s):  
Cellular Response ◽  
Physical Nature ◽  
Cell Types ◽  
Artificial Substrates ◽  
Adherent Cell ◽  
Fibrillar Collagen ◽  
New Materials ◽  
Substrate Interactions ◽  
Number Of Factors ◽  
Cell Substrate

Adherent cells generally construct the immediate substrate upon which they reside. This may occur via synthesis and secretion of new materials and/or by rearrangement and modification of existing substrate. The response of adherent cell types to an existing substrate can be influenced by a number of factors which include both the chemical and physical nature of the substrate. Cell adhesion, proliferation, differentiation and death can all be substrate dependent. Much effort has been directed toward chemical modification of substrates to regulate one or more of the parameters noted above. A significant, but somewhat smaller, degree of attention has been paid to the effects of the topography and microtopography on the cell response to substrate materials. Studies to date strongly suggest the topography is a significant factor in cell-substrate interactions. As noted above, it is most probable that both the chemistry and the structure of a substrate simultaneously influence the cellular response. However we wished to determine, particularly for artificial substrates, the role which microtopography can play in cell-substrate interactions.

Sign in / Sign up

Export Citation Format

Share Document