Mechanical stretch‐induced endoplasmic reticulum stress, apoptosis and inflammation contribute to thoracic aortic aneurysm and dissection

<jats:title>Abstract</jats:title><jats:p>Thoracic aortic aneurysm/dissection (<jats:styled-content style="fixed-case">TAAD</jats:styled-content>) is characterized by excessive smooth muscle cell (<jats:styled-content style="fixed-case">SMC</jats:styled-content>) loss, extracellular matrix (<jats:styled-content style="fixed-case">ECM</jats:styled-content>) degradation and inflammation. In response to certain stimuli, endoplasmic reticulum (<jats:styled-content style="fixed-case">ER</jats:styled-content>) stress is activated and regulates apoptosis and inflammation. Excessive apoptosis promotes aortic inflammation and degeneration, leading to <jats:styled-content style="fixed-case">TAAD</jats:styled-content>. Therefore, we studied the role of <jats:styled-content style="fixed-case">ER</jats:styled-content> stress in <jats:styled-content style="fixed-case">TAAD</jats:styled-content> formation. A lysyl oxidase inhibitor, 3‐aminopropionitrile fumarate (<jats:styled-content style="fixed-case">BAPN</jats:styled-content>), was administrated to induce <jats:styled-content style="fixed-case">TAAD</jats:styled-content> formation in mice, which showed significant <jats:styled-content style="fixed-case">SMC</jats:styled-content> loss (α‐<jats:styled-content style="fixed-case">SMA</jats:styled-content> level). Excessive apoptosis (<jats:styled-content style="fixed-case">TUNEL</jats:styled-content> staining) and <jats:styled-content style="fixed-case">ER</jats:styled-content> stress (<jats:styled-content style="fixed-case">ATF4</jats:styled-content> and <jats:styled-content style="fixed-case">CHOP</jats:styled-content>), along with inflammation, were present in <jats:styled-content style="fixed-case">TAAD</jats:styled-content> samples from both mouse and human. Transcriptional profiling of <jats:styled-content style="fixed-case">SMCs</jats:styled-content> after mechanical stress demonstrated the expression of genes for <jats:styled-content style="fixed-case">ER</jats:styled-content> stress and inflammation. To explore the causal role of <jats:styled-content style="fixed-case">ER</jats:styled-content> stress in initiating degenerative signalling events and <jats:styled-content style="fixed-case">TAAD</jats:styled-content>, we treated wild‐type (<jats:italic><jats:styled-content style="fixed-case">CHOP</jats:styled-content></jats:italic><jats:sup>+/+</jats:sup>) or <jats:italic><jats:styled-content style="fixed-case">CHOP</jats:styled-content></jats:italic><jats:sup>−/−</jats:sup> mice with <jats:styled-content style="fixed-case">BAPN</jats:styled-content> and found that <jats:italic><jats:styled-content style="fixed-case">CHOP</jats:styled-content></jats:italic> deficiency protected against <jats:styled-content style="fixed-case">TAAD</jats:styled-content> formation and rupture, as well as reduction in α‐<jats:styled-content style="fixed-case">SMA</jats:styled-content> level. Both <jats:styled-content style="fixed-case">SMC</jats:styled-content> apoptosis and inflammation were significantly reduced in <jats:italic><jats:styled-content style="fixed-case">CHOP</jats:styled-content></jats:italic><jats:sup>−/−</jats:sup> mice. Moreover, <jats:styled-content style="fixed-case">SMCs</jats:styled-content> isolated from <jats:italic><jats:styled-content style="fixed-case">CHOP</jats:styled-content></jats:italic><jats:sup>−/−</jats:sup> mice were resistant to mechanical stress‐induced apoptosis<jats:italic>.</jats:italic> Taken together, our results demonstrated that mechanical stress‐induced <jats:styled-content style="fixed-case">ER</jats:styled-content> stress promotes <jats:styled-content style="fixed-case">SMCs</jats:styled-content> apoptosis, inflammation and degeneration, providing insight into <jats:styled-content style="fixed-case">TAAD</jats:styled-content> formation and progression. © 2015 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.</jats:p>