Fibroblasts in atherosclerosis: heterogeneous and plastic participants

Tillie, Renée J H A; Kuijk, Kim van; Sluimer, Judith C.

doi:10.1097/mol.0000000000000700

Cited by 29 publications

(32 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…With the development and increasing popularity of single cell RNA sequencing technology, it might now be possible to find markers, specific to adventitial fibroblasts, as well as to characterize in depth, their subpopulations in normal and diseased states [30]. Kalluri et al [31] explored the cellular atlas of healthy mice aortas using single cell RNA sequencing.…”

Section: Fibroblasts In Healthy Arterial Vessel Wallsmentioning

confidence: 99%

The Role of Fibroblasts in Atherosclerosis Progression

Kuret¹,

Sodin‐Šemrl²

2021

Biochemistry

View full text Add to dashboard Cite

The following chapter addresses vascular fibroblasts in a healthy, quiescent state, as well during vascular inflammation, focusing on atherosclerosis. The development of atherosclerosis, an inflammatory disease of medium- and large-sized arteries, has traditionally been viewed as an “inside-out” mechanism, with prominent roles of the innermost layer of the artery, consisting of endothelial cells. However, emerging evidence suggests a new paradigm of “outside-in” mechanism, including an earlier role for fibroblasts, constituents of the outermost adventitial layer of the artery. Phenotypic and functional changes of fibroblasts in adventitia may even occur prior to, or alongside endothelial activation. Activated adventitial fibroblasts, implicated in atherosclerosis progression, begin to transform into myofibroblasts, upregulate production of different proinflammatory cytokines, chemokines, growth factors, proteolytic enzymes, extracellular matrix proteins and reactive oxygen species, leading to extensive matrix remodeling, chemotaxis and recruitment of immune cells. Due to their suitable location for drug delivery systems, preventing fibroblast activation, modulating their activity or inducing myofibroblast dedifferentiation could represent a promising therapeutic approach for atherosclerosis regression.

show abstract

Section: Fibroblasts In Healthy Arterial Vessel Wallsmentioning

confidence: 99%

The Role of Fibroblasts in Atherosclerosis Progression

Kuret¹,

Sodin‐Šemrl²

2021

Biochemistry

View full text Add to dashboard Cite

show abstract

“…VSMC that infiltrate the intima lose αSMA expression when transdifferentiating to macrophage-like cells [ 38 ], and VSMC in the media impact lesion formation by cell death, being replaced with extracellular matrix, and by increasing LDL deposition in the plaque [ 39 , 40 ]. Fibroblasts, mostly located in the adventitia, are sources of inflammatory cytokines and growth factors [ 41 , 42 ], as are B-cells, which also serve as antigen-presenting cells secreting antibodies [ 43 , 44 ]. Our single-cell analysis reveals that IRF5 is expressed in these atheroma-associated cell types besides monocytes and macrophages, albeit at lower levels.…”

Section: Discussionmentioning

confidence: 99%

Myeloid cell-specific Irf5 deficiency stabilizes atherosclerotic plaques in Apoe mice

Leipner

Dederichs

Ehr

et al. 2021

Molecular Metabolism

View full text Add to dashboard Cite

Objective Interferon regulatory factor (IRF) 5 is a transcription factor known for promoting M1 type macrophage polarization in vitro . Given the central role of inflammatory macrophages in promoting atherosclerotic plaque progression, we hypothesize that myeloid cell-specific deletion of IRF5 is protective against atherosclerosis. Methods Female Apoe –/– Lysm Cre/+ Irf5 fl/fl and Apoe −/− Irf5 fl/fl mice were fed a high-cholesterol diet for three months. Atherosclerotic plaque size and compositions as well as inflammatory gene expression were analyzed. Mechanistically, IRF5-dependent bone marrow-derived macrophage cytokine profiles were tested under M1 and M2 polarizing conditions. Mixed bone marrow chimeras were generated to determine intrinsic IRF5-dependent effects on macrophage accumulation in atherosclerotic plaques. Results Myeloid cell-specific Irf5 deficiency blunted LPS/IFNγ-induced inflammatory gene expression in vitro and in the atherosclerotic aorta in vivo . While atherosclerotic lesion size was not reduced in myeloid cell-specific Irf5 -deficient Apoe –/– mice, plaque composition was favorably altered, resembling a stable plaque phenotype with reduced macrophage and lipid contents, reduced inflammatory gene expression and increased collagen deposition alongside elevated Mertk and Tgfβ expression. Irf5- deficient macrophages, when directly competing with wild type macrophages in the same mouse, were less prone to accumulate in atherosclerotic lesion, independent of monocyte recruitment. Irf5 -deficient monocytes, when exposed to oxidized low density lipoprotein, were less likely to differentiate into macrophage foam cells, and Irf5 -deficient macrophages proliferated less in the plaque. Conclusion Our study provides genetic evidence that selectively altering macrophage polarization induces a stable plaque phenotype in mice.

show abstract

“…It may be perceived that bidirectional stress for cardiac cells from the periphery to the heart and vice versa strongly contributes to atherosclerotic CAD [ 26 , 27 ]. Keep in mind that atherosclerotic lesions are more common at branching sites which are most often exposed to various types of stress such as hyperlipidemia and blood flow disruption [ 21 , 28 ]. Thus, a more comprehensive view of the cellular stress response to atherosclerosis may open a new horizon into a better understanding of the pathophysiology of the disease as well as the discovery of new diagnostic markers and the development of efficient therapeutic strategies.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, fibroblasts constitute 60-70% of the cardiac cells and play an important role in the health or disease of the cardiovascular system [ 19 , 20 ]. Also, fibroblasts account for about 33% of aortic cells in mice that play critical functions in tissue homeostasis [ 21 ]. In addition, different numbers of fibroblast clusters have been observed in both healthy and atherosclerotic tissues [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

“…Also, fibroblasts account for about 33% of aortic cells in mice that play critical functions in tissue homeostasis [ 21 ]. In addition, different numbers of fibroblast clusters have been observed in both healthy and atherosclerotic tissues [ 21 ]. On the other hand, Golpour et al have shown that serum starvation can significantly induce the production of more than 90 different proteins with cell survival and cell growth-promoting properties by human skin fibroblasts [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Patients with Coronary Artery Disease Have Lower Levels of Antibody to Heat-Stressed Fibroblast Derived Proteins, versus Normal Subjects

Aghamajidi

Khameneh

Amirjamshidi

et al. 2021

Cardiovascular Therapeutics

View full text Add to dashboard Cite

Cellular stress response plays an important role in the pathophysiology of coronary artery disease (CAD). Inhibition of cellular stress may provide a novel clinical approach regarding the diagnosis and treatment of CAD. Fibroblasts constitute 60-70% of cardiac cells and have a crucial role in cardiovascular function. Hence, the aim of this study was to show a potential therapeutic application of proteins derived from heat-stressed fibroblast in CAD patients. Fibroblasts were isolated from the foreskin and cultured under heat stress conditions. Surprisingly, 1.06% of the cells exhibited a necrotic death pattern. Furthermore, heat-stressed fibroblasts produced higher level of total proteins than control cells. In SDS-PAGE analysis, a 70 kDa protein band was observed in stressed cell culture supernatants which appeared as two acidic spots with close pI in the two-dimensional electrophoresis. To evaluate the immunogenic properties of fibroblast-derived heat shock proteins (HSPs), the serum immunoglobulin-G (IgG) was measured by ELISA in 50 CAD patients and 50 normal subjects who had been diagnosed through angiography. Interestingly, the level of anti-HSP antibody was significantly higher in non-CAD individuals in comparison with the patient’s group ( p < 0.05 ). The odds ratio for CAD was 5.06 ( 95 % CI = 2.15 ‐ 11.91 ) in cut-off value of 30 AU/mL of anti-HSP antibody. Moreover, ROC analysis showed that anti-HSP antibodies had a specificity of 74% and a sensitivity of 64%, which is almost equal to 66% sensitivity of exercise stress test (EST) as a CAD diagnostic method. These data revealed that fibroblast-derived HSPs are suitable for the diagnosis and management of CAD through antibody production.

show abstract

Fibroblasts in atherosclerosis: heterogeneous and plastic participants

Cited by 29 publications

References 33 publications

The Role of Fibroblasts in Atherosclerosis Progression

The Role of Fibroblasts in Atherosclerosis Progression

Myeloid cell-specific Irf5 deficiency stabilizes atherosclerotic plaques in Apoe mice

Patients with Coronary Artery Disease Have Lower Levels of Antibody to Heat-Stressed Fibroblast Derived Proteins, versus Normal Subjects

Contact Info

Product

Resources

About