scholarly journals ER stress dependent microparticles derived from smooth muscle cells promote endothelial dysfunction during thoracic aortic aneurysm and dissection

2017 ◽  
Vol 131 (12) ◽  
pp. 1287-1299 ◽  
Author(s):  
Li-Xin Jia ◽  
Wen-Mei Zhang ◽  
Tao-Tao Li ◽  
Yan Liu ◽  
Chun-Mei Piao ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Endothelial Dysfunction ◽  
Aortic Aneurysm ◽  
Er Stress ◽  
Thoracic Aortic Aneurysm ◽  
Mechanical Stretch ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Aortic Aneurysm And Dissection ◽  
Stress Dependent

The degeneration of vascular smooth muscle cell(s) (SMC) is one of the key features of thoracic aortic aneurysm and dissection (TAAD). We and others have shown that elevated endoplasmic reticulum (ER) stress causes SMC loss and TAAD formation, however, the mechanism of how SMC dysfunction contributes to intimal damage, leading to TAAD, remains to be explored. In the present study, in vitro assay demonstrated that elevated mechanical stretch (18% elongation, 3600 cycles/h) stimulated the ER stress response and microparticle(s) (MP) production from both SMC and endothelial cell(s) (EC) in a time-dependent manner. Treatment of EC with isolated MP led to anoikis, which was determined by measuring the fluorescence of the ethidium homodimer (EthD-1) and Calcein AM cultured in hydrogel-coated plates and control plates. MP stimulation of EC also up-regulated the mRNA levels of inflammatory molecules (i.e. Vascular cellular adhesion molecular-1 (VCAM-1)), intercellular adhesion molecular-1 (ICAM-1), interleukin-1β (IL-1β), and interleukin-6 (IL-6)). Use of an ER stress inhibitor or knockout of CHOP decreased mechanical stretch-induced MP production in SMC. In vivo, administration of an ER stress inhibitor or knockout of CHOP suppressed both apoptosis of EC and the infiltration of inflammatory cells. Moreover, TAAD formation was also suppressed by the administration of an ER stress inhibitor. In conclusion, our study demonstrates that elevated mechanical stretch induces MP formation in SMC leading to endothelial dysfunction, which is ER stress dependent. The inhibition of ER stress suppressed EC apoptosis, inflammation in the aorta, and TAAD development.

scholarly journals Endoplasmic Reticulum Stress Mediates Vascular Smooth Muscle Cell Calcification via Increased Release of Grp78-Loaded Extracellular Vesicles

2020 ◽  
Author(s):  
Malgorzata Furmanik ◽  
Rick van Gorp ◽  
Meredith Whitehead ◽  
Sadia Ahmad ◽  
Jayanta Bordoloi ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Er Stress ◽  
Vascular Calcification ◽  
Bone Mineralization ◽  
Extracellular Vesicle ◽  
Dependent Manner ◽  
The Matrix ◽  
Stress Dependent

Objective: Vascular calcification is common among aging populations and mediated by vascular smooth muscle cells (VSMCs). The endoplasmic reticulum (ER) is involved in protein folding and ER stress has been implicated in bone mineralization. The role of ER stress in VSMC-mediated calcification is less clear. Approach and Results: mRNA expression of the ER stress markers PERK (PKR (protein kinase RNA)-like ER kinase), ATF (activating transcription factor) 4, ATF6, and Grp78 was detectable in human vessels with levels of PERK decreased in calcified plaques compared to healthy vessels. Protein deposition of Grp78/Grp94 was increased in the matrix of calcified arteries. Induction of ER stress accelerated human primary VSMC-mediated calcification, elevated expression of some osteogenic markers (Runx2, Osterix, ALP, BSP, and OPG), and decreased expression of SMC markers. ER stress potentiated extracellular vesicle (EV) release via SMPD3. EVs from ER stress-treated VSMCs showed increased Grp78 levels and calcification. Electron microscopy confirmed the presence of Grp78/Grp94 in EVs. siRNA knock-down of Grp78 decreased calcification. Warfarin-induced Grp78 and ATF4 expression in rat aortas and VSMCs and increased calcification in an ER stress-dependent manner via increased EV release. Conclusions: ER stress induces vascular calcification by increasing release of Grp78-loaded EVs. Our results reveal a novel mechanism of action of warfarin, involving increased EV release via the PERK-ATF4 pathway, contributing to calcification. This study is the first to show that warfarin induces ER stress and to link ER stress to cargo loading of EVs.

scholarly journals Genes Associated with Thoracic Aortic Aneurysm and Dissection

Aorta ◽  
2017 ◽  
Vol 05 (01) ◽  
pp. 11-20 ◽  
Author(s):  
Adam Brownstein ◽  
Bulat Ziganshin ◽  
Helena Kuivaniemi ◽  
Simon Body ◽  
Allen Bale ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Smooth Muscle ◽  
Aortic Aneurysm ◽  
Thoracic Aortic Aneurysm ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Functional Assays ◽  
Aortic Aneurysm And Dissection ◽  
History Of ◽  
Generation Sequencing

AbstractThoracic aortic aneurysm (TAA) is a lethal disease, with a natural history of enlarging progressively until dissection or rupture occurs. Since the discovery almost 20 years ago that ascending TAAs are highly familial, our understanding of the genetics of thoracic aortic aneurysm and dissection (TAAD) has increased exponentially. At least 29 genes have been shown to be associated with the development of TAAD, the majority of which encode proteins involved in the extracellular matrix, smooth muscle cell contraction or metabolism, or the transforming growth factor-β signaling pathway. Almost one-quarter of TAAD patients have a mutation in one of these genes. In this review, we provide a summary of TAAD-associated genes, associated clinical features of the vasculature, and implications for surgical treatment of TAAD. With the widespread use of next-generation sequencing and development of novel functional assays, the future of the genetics of TAAD is bright, as both novel TAAD genes and variants within the genes will continue to be identified.

scholarly journals Allele-specific Effects of Thoracic Aortic Aneurysm and Dissection α-Smooth Muscle Actin Mutations on Actin Function

2011 ◽  
Vol 286 (13) ◽  
pp. 11356-11369 ◽  
Author(s):  
Sarah E. Bergeron ◽  
Elesa W. Wedemeyer ◽  
Rose Lee ◽  
Kuo-Kuang Wen ◽  
Melissa McKane ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Aortic Aneurysm ◽  
Thoracic Aortic Aneurysm ◽  
Smooth Muscle Actin ◽  
Muscle Actin ◽  
Specific Effects ◽  
Aortic Aneurysm And Dissection ◽  
Allele Specific

Obstruction stimulates COX-2 expression in bladder smooth muscle cells via increased mechanical stretch

1999 ◽  
Vol 276 (1) ◽  
pp. F129-F136 ◽  
Author(s):  
John M. Park ◽  
Tianxin Yang ◽  
Lois J. Arend ◽  
Jürgen B. Schnermann ◽  
Craig A. Peters ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Outlet Obstruction ◽  
Muscle Cells ◽  
Mechanical Stretch ◽  
Type I ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Bladder Smooth Muscle ◽  
Cox 2

Studies were performed to investigate the regulatory mechanism of bladder cyclooxygenase-2 (COX-2) expression after outlet obstruction. In situ hybridization of murine bladder tissues using COX-2-specific riboprobes demonstrated that COX-2 expression was induced predominantly in the bladder smooth muscle cells after outlet obstruction. To study the effect of increased mechanical stretch on COX isoform expression, cultured rat bladder smooth muscle cells were grown on silicone elastomer-bottomed plates coated with collagen type I and were subjected to continuous cycles of stretch/relaxation for variable duration. COX-1 mRNA levels did not change with stretch. COX-2 expression increased in a time-dependent manner after stretch, with maximal mRNA and protein levels occurring after 4 h. PGE2 levels increased more than 40-fold in the culture media after stretch, consistent with increased COX activity, and this was reduced to near completion in the presence of a COX-2 inhibitor, NS-398. Exposure to stretch over a 48-h period induced a 4.7 ± 0.6-fold increase in tritiated thymidine incorporation rate. This increase in DNA synthesis was markedly suppressed when the cells were stretched in the presence of NS-398. We conclude that in bladder obstruction COX-2 activation occurs predominantly in the smooth muscle cells in response to mechanical stretch. Our findings also suggest that stretch-activated COX-2 expression may participate in bladder smooth muscle cell proliferation and thereby play a role in pathological bladder wall thickening after obstruction.

scholarly journals MUTATIONS IN SMOOTH MUSCLE AORTIC ALPHA-ACTIN GENE ARE ASSOCIATED WITH FAMILIAL THORACIC AORTIC ANEURYSM AND DISSECTION

2015 ◽  
Vol 65 (10) ◽  
pp. A2060
Author(s):  
Nupoor Narula ◽  
Eliana Disabella ◽  
Valentina Favalli ◽  
Alessandra Serio ◽  
Maurizia Grasso ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Aortic Aneurysm ◽  
Thoracic Aortic Aneurysm ◽  
Actin Gene ◽  
Aortic Aneurysm And Dissection ◽  
Alpha Actin

scholarly journals A post mortem assessment of a 25-year-old man with ascending aortic dissection and a novel MYLK variant

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Katelyn Hodge ◽  
Katherine G. Spoonamore ◽  
Christopher B. Griffith ◽  
David D. Weaver ◽  
Patricia B.S. Celestino-Soper ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Aortic Aneurysm ◽  
Aortic Dissection ◽  
Thoracic Aortic Aneurysm ◽  
Aortic Rupture ◽  
Clinical Consequence ◽  
Post Mortem ◽  
Variant Of Uncertain Significance ◽  
Pathogenic Variants ◽  
Aortic Aneurysm And Dissection

We report on the process of <em>post mortem</em> evaluation and genetic testing following the death of a 25-year-old man due to ascending aortic dissection leading to aortic rupture. Following the negative clinical testing of a 12- gene thoracic aortic aneurysm and dissection panel, research testing revealed a novel c.5732A&gt;T (p.E1911V) variant in exon 34 of the MYLK gene (NM_053025). Two likely pathogenic variants in this gene have been reported previously in individuals with familial thoracic aortic aneurysm and dissection. Given the unclear clinical consequence of the variant found in our proband, we have classified this change as a variant of uncertain significance. In addition to discussing the complexity involved in variant interpretation, we recognize the need for additional research for more accurate <em>MYLK</em> interpretation. Finally, we comment on the unique challenges of <em>post mortem</em> genetic testing.

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