Accelerated atherosclerosis in HGPS

Hamczyk, Magda R.; Andrés, Vicente

doi:10.18632/aging.101608

Cited by 5 publications

(11 citation statements)

References 7 publications

(11 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A series of diseases termed laminopathies are associated with mutations of A-type lamins, including Hutchinson-Gilford progeria, striated muscle diseases, neuropathies, and lipodystrophies [32,33]. Recently, Hutchinson-Gilford progeria syndrome (HGPS) has provided an excellent model system for researchers, because HGPS shows accelerated aging as well as important bone changes that include severe osteoporosis and bone deformities [34][35][36]. LAP2α downregulation has been proven to be a characteristic of the HGPS cellular phenotype in previous studies [14,15]; therefore, we hypothesized that LAP2α might play a role in MSC differentiation into osteoblasts.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of LAP2α inhibits osteogenic differentiation of human adipose-derived stem cells by activating NF-κB

Tang

Zhang

et al. 2020

Stem Cell Res Ther

View full text Add to dashboard Buy / Rent full text

Background: Lamina-associated polypeptide 2α (LAP2α) is a nucleoplasmic protein that has been involved in the regulation of the cell cycle, gene transcription, and adult stem cell function. LAP2α down-regulation is linked to age-related osteoporosis and bone deformities; however, the underlying mechanisms remain obscure. The present study aimed to elucidate the function of LAP2α in the osteogenic differentiation of human adipose-derived stem cells (hASCs), which are attractive sources for bone tissue engineering. Methods: The expression of LAP2α during the osteogenic differentiation of hASCs was detected firstly. A loss of function investigation was then carried out to characterize the function of LAP2α in osteogenic differentiation of hASCs both in vitro and in vivo. Moreover, RNA-sequences, western blotting, and confocal analyses were performed to clarify the molecular mechanism of LAP2α-regulated osteogenesis. Results: We found that LAP2α expression was upregulated upon osteogenic induction. Both in vitro and in vivo experiments indicated that LAP2α knockdown resulted in impaired osteogenic differentiation of hASCs. Mechanistically, we revealed that LAP2α deficiency activated nuclear factor kappa B (NF-κB) signaling by controlling the cytoplasmic-nuclear translocation of p65. Conclusions: Collectively, our findings revealed that LAP2α functions as an essential regulator for osteogenesis of hASCs by modulating NF-κB signaling, thus providing novel insights for mesenchymal stem cell-mediated bone tissue engineering.

show abstract

Section: Discussionmentioning

confidence: 99%

Knockdown of LAP2α inhibits osteogenic differentiation of human adipose-derived stem cells by activating NF-κB

Tang

Zhang

et al. 2020

Stem Cell Res Ther

View full text Add to dashboard Buy / Rent full text

show abstract

“…In HGPS patients, scleroderma, aging of skin and bone defects are generally observed [ 2 ]. With the progression of the disease, some patients suffer other HGPS-associated symptoms such as accelerated arteriosclerosis, kidney failure, and cardiovascular problems [ 2 – 4 ]. Most patients die from heart attacks and strokes because of atherosclerotic disease and myocardial infarction [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Impairment of nuclear F-actin formation and its relevance to cellular phenotypes in Hutchinson-Gilford progeria syndrome

Takahashi

Hiratsuka

Machida

et al. 2020

Nucleus

View full text Add to dashboard Buy / Rent full text

Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder caused by a mutation of lamin A, which contributes to nuclear architecture and the spatial organization of chromatin in the nucleus. The expression of a lamin A mutant, named progerin, leads to functional and structural disruption of nuclear organization. Since progerin lacks a part of the actin-binding site of lamin A, we hypothesized that nuclear actin dynamics and function are altered in HGPS cells. Nuclear F-actin is required for the organization of nuclear shape, transcriptional regulation, DNA damage repair, and activation of Wnt/β-catenin signaling. Here we show that the expression of progerin decreases nuclear F-actin and impairs F-actin-regulated transcription. When nuclear F-actin levels are increased by overexpression of nuclear-targeted actin or by using jasplakinolide, a compound that stabilizes F-actin, the irregularity of nuclear shape and defects in gene expression can be reversed. These observations provide evidence for a novel relationship between nuclear actin and the etiology of HGPS.

show abstract

“…The lack of co-localization of IRF5 expression and αSMA in atherosclerotic lesions, shown by Seneviratne et al., does not preclude that IRF5 can function in vascular smooth muscle cells (VSMC) in atherosclerotic lesions. 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 ].…”

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 Buy / Rent full text

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

Accelerated atherosclerosis in HGPS

Cited by 5 publications

References 7 publications

Knockdown of LAP2α inhibits osteogenic differentiation of human adipose-derived stem cells by activating NF-κB

Knockdown of LAP2α inhibits osteogenic differentiation of human adipose-derived stem cells by activating NF-κB

Impairment of nuclear F-actin formation and its relevance to cellular phenotypes in Hutchinson-Gilford progeria syndrome

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

Contact Info

Product

Resources

About