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

Abstract

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.

• Authors: Li-Xin Jia, Wen-Mei Zhang, Tao-Tao Li, Yan Liu, Chun-Mei Piao, You-Cai Ma, Yu Lu, Yuan Wang, Ting-Ting Liu, Yong-Fen Qi, Jie Du
• Journal: Clinical science (London, England : 1979) (Clin Sci (Lond)) Vol. 131 Issue 12 Pg. 1287-1299 (Jun 01 2017) ISSN: 1470-8736 [Electronic] England
• PMID: 28468950 (Publication Type: Journal Article)
• Copyright: © 2017 The Author(s).

Chemical References

• Ddit3 protein, mouse
• Inflammation Mediators
• RNA, Messenger
• Transcription Factor CHOP
• Aminopropionitrile

Topics

• Aminopropionitrile
• Aortic Dissection (chemically induced, genetics, metabolism, pathology)
• Animals
• Anoikis
• Aorta, Thoracic (metabolism, pathology)
• Aortic Aneurysm, Thoracic (chemically induced, genetics, metabolism, pathology)
• Cell-Derived Microparticles (metabolism, pathology)
• Cells, Cultured
• Disease Models, Animal
• Endoplasmic Reticulum (metabolism, pathology)
• Endoplasmic Reticulum Stress
• Endothelial Cells (metabolism, pathology)
• Gene Expression Regulation
• Genetic Predisposition to Disease
• Humans
• Inflammation Mediators (metabolism)
• Male
• Mechanotransduction, Cellular
• Mice, Inbred C57BL
• Mice, Knockout
• Muscle, Smooth, Vascular (metabolism, pathology)
• Myocytes, Smooth Muscle (metabolism, pathology)
• Paracrine Communication
• Phenotype
• RNA, Messenger (genetics)
• Stress, Mechanical
• Time Factors
• Transcription Factor CHOP (genetics, metabolism)