Fibroblasts and Their Pathological Functions in the Fibrosis of Aortic Valve Sclerosis and Atherosclerosis

Singh, Sandeep; Torzewski, Michael

doi:10.3390/biom9090472

Cited by 58 publications

(48 citation statements)

References 101 publications

(107 reference statements)

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“…Oxidative stress is defined as excessive reactive oxygen species (ROS) relative to antioxidant defenses, and is advanced in HF ( 50 ). ROS can mediate cell apoptosis and MMPs, leading to ECM remodeling ( 51 ). MMP3 and MMP9 are extracellular zinc proteases that serve vital roles in the development and progression of atherosclerosis ( 52 ).…”

Section: Discussionmentioning

confidence: 99%

Matrix metalloproteinase 3 regulates angiotensin II‑induced myocardial fibrosis cell viability, migration and apoptosis

Jin

et al. 2020

Mol Med Rep

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Angiotensin II (AngII) is a central signaling molecule of the renin-angiotensin system that serves a vital role in myocardial fibrosis (MF). The present study aimed to investigate the effects of matrix metalloproteinase (MMP)3 on MF progression. To induce cellular fibrosis, H9C2 rat myocardial cells were treated with AngII for 24 h. Subsequently, cells were treated with levocarnitine, or transfected with small interfering (si)RNA-negative control or siRNA-MMP3 (1/2/3). Cell viability, apoptosis and migration were assessed by performing Cell Counting Kit-8, flow cytometry and Transwell assays, respectively. Reverse transcription-quantitative PCR (RT-qPCR) and western blotting were performed to determine the expression levels of MF biomarkers, including disease-, apoptosis-and oxidative stress-related genes. Compared with the control group, AngII significantly inhibited H9C2 cell viability and migration, and significantly increased H9C2 cell apoptosis (P<0.05). However, compared with AngII-treated H9C2 cells, MMP3 knockdown significantly inhibited fibrotic H9C2 cell viability and migration, but increased fibrotic H9C2 cell apoptosis (P<0.05). The RT-qPCR results demonstrated that MMP3 knockdown significantly downregulated the expression levels of AXL receptor tyrosine kinase, AngII receptor type 1, α-smooth muscle actin and Collagen I in AngII-treated H9C2 cells (P<0.05). Moreover, compared with AngII-treated cells, MMP3 knockdown significantly decreased Bcl-2 expression levels , but significantly increased caspase-3 and p53 expression levels in AngII-treated cells (P<0.05). Additionally, compared with AngII-treated cells, MMP3 knockdown significantly decreased MMP3, MMP9, STAT3, p22Phox and p47Phox expression levels in AngII-treated cells (P<0.05). The present study indicated that MMP3 knockdown altered myocardial fibroblast cell viability, migration and apoptosis by regulating apoptosis-and oxidative stress-related genes, thus delaying MF progression.

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Section: Discussionmentioning

confidence: 99%

Matrix metalloproteinase 3 regulates angiotensin II‑induced myocardial fibrosis cell viability, migration and apoptosis

Jin

et al. 2020

Mol Med Rep

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“…These cytokines cause both paracrine and endocrine effects that mediate local and systemic responses [28,29]). According to a recent review [30], the expression of pro-inflammatory cytokines, such as TGF-β, TNFα, IL-1β, and IL-6, is consistently identified in aortic-valve sclerosis. These cytokines seem to be produced by leaflets' activated fibroblasts, whose differentiation, proliferation, and matrix remodeling participate in the endothelial damage of aortic valve leading to the valve thickening [30].…”

Section: Discussionmentioning

confidence: 99%

“…According to a recent review [30], the expression of pro-inflammatory cytokines, such as TGF-β, TNFα, IL-1β, and IL-6, is consistently identified in aortic-valve sclerosis. These cytokines seem to be produced by leaflets' activated fibroblasts, whose differentiation, proliferation, and matrix remodeling participate in the endothelial damage of aortic valve leading to the valve thickening [30]. IL-6 is also known to be involved in the endothelial dysfunction of other cardiovascular diseases by interfering with endothelial nitric oxide synthase expression [31] and, in conjunction with C-reactive protein, is regarded as an indicator of chronic or systemic low-grade inflammation [18].…”

Section: Discussionmentioning

confidence: 99%

Inflammation and Reduced Parasympathetic Cardiac Modulation in Aortic-Valve Sclerosis

et al. 2019

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Aortic-valve sclerosis increases cardiovascular mortality risk and precedes aortic-valve stenosis, but its mechanisms are not well understood. The purpose of this study was to compare the cardiac autonomic modulation and inflammation markers between subjects with aortic-valve normal leaflets and subjects with aortic-valve sclerosis. According to 2-D transthoracic echocardiograms, 61 middle-aged volunteers without chronic or acute illnesses were classified in two groups: with no aortic-valve sclerosis (NAVS, N = 16) and with aortic-valve sclerosis (AVS, N = 45). An electrocardiogram at the supine position and active standing was collected to estimate heart rate variability (HRV) indices. A blood sample was obtained to quantify markers of inflammation. Compared to NAVS, AVS subjects showed higher levels of IL-6 (1619 ± 650 vs. 1169 ± 676 pg/mL, p = 0.044) as well as TNFα (370.8 ± 182.0 vs. 247.3 ± 188.2 pg/mL, p = 0.032), and larger low-frequency (LF) to high-frequency (HF) ratio during supine position (Ln(LF/HF) = 0.85 ± 0.85 vs. 0.11 ± 0.69, p = 0.003). Multiple logistic regression analysis showed that AVS was independently associated with LF/HF, TNFα and left ventricle mass index (p < 0.05). In conclusion, a significant reduction of the parasympathetic-driven cardiac modulation and low-grade inflammation occurs in aortic-valve sclerosis.

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“…Liu et al [ 16 ] distinguished five phenotypes in the VICs family: embryonic progenitor endothelial/mesenchymal cells, quiescent VICs (qVICs), activated VICs (aVICs), progenitor VICs (pVICs), and osteoblastic VICs (obVICs). The cytological features of activated VICs (aVICs) correspond to those of myofibroblasts, described in valves by numerous authors and reported to play an important role in valve fibrosis contributing to degenerative processes such as valve sclerosis and atherosclerosis [ 23 ]. However, Combs et al claimed that neither the commitment of VICs to the separate, fixed lineages nor the specific origin of VIC in distinct valve compartments have been unequivocally defined and proved [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of CD34+/PGDFRα+ Valve Interstitial Cells (VICs) in Human Aortic Valves: Association of Their Abundance, Morphology and Spatial Organization with Early Calcific Remodeling

Lis

Dubrowski

Lis

et al. 2020

IJMS

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Aortic valve interstitial cells (VICs) constitute a heterogeneous population involved in the maintenance of unique valvular architecture, ensuring proper hemodynamic function but also engaged in valve degeneration. Recently, cells similar to telocytes/interstitial Cajal-like cells described in various organs were found in heart valves. The aim of this study was to examine the density, distribution, and spatial organization of a VIC subset co-expressing CD34 and PDGFRα in normal aortic valves and to investigate if these cells are associated with the occurrence of early signs of valve calcific remodeling. We examined 28 human aortic valves obtained upon autopsy. General valve morphology and the early signs of degeneration were assessed histochemically. The studied VICs were identified by immunofluorescence (CD34, PDGFRα, vimentin), and their number in standardized parts and layers of the valves was evaluated. In order to show the complex three-dimensional structure of CD34+/PDGFRα+ VICs, whole-mount specimens were imaged by confocal microscopy, and subsequently rendered using the Imaris (Bitplane AG, Zürich, Switzerland) software. CD34+/PDGFRα+ VICs were found in all examined valves, showing significant differences in the number, distribution within valve tissue, spatial organization, and morphology (spherical/oval without projections; numerous short projections; long, branching, occasionally moniliform projections). Such a complex morphology was associated with the younger age of the subjects, and these VICs were more frequent in the spongiosa layer of the valve. Both the number and percentage of CD34+/PDGFRα+ VICs were inversely correlated with the age of the subjects. Valves with histochemical signs of early calcification contained a lower number of CD34+/PDGFRα+ cells. They were less numerous in proximal parts of the cusps, i.e., areas prone to calcification. The results suggest that normal aortic valves contain a subpopulation of CD34+/PDGFRα+ VICs, which might be involved in the maintenance of local microenvironment resisting to pathologic remodeling. Their reduced number in older age could limit the self-regenerative properties of the valve stroma.

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Fibroblasts and Their Pathological Functions in the Fibrosis of Aortic Valve Sclerosis and Atherosclerosis

Cited by 58 publications

References 101 publications

Matrix metalloproteinase 3 regulates angiotensin II‑induced myocardial fibrosis cell viability, migration and apoptosis

Matrix metalloproteinase 3 regulates angiotensin II‑induced myocardial fibrosis cell viability, migration and apoptosis

Inflammation and Reduced Parasympathetic Cardiac Modulation in Aortic-Valve Sclerosis

Identification of CD34+/PGDFRα+ Valve Interstitial Cells (VICs) in Human Aortic Valves: Association of Their Abundance, Morphology and Spatial Organization with Early Calcific Remodeling

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