title: Mechanical stretch-induced endoplasmic reticulum stress, apoptosis and inflammation contribute to thoracic aortic aneurysm and dissection.
abstract: Thoracic aortic aneurysm/dissection (TAAD) is characterized by excessive smooth muscle cell (SMC) loss, extracellular matrix (ECM) degradation and inflammation. In response to certain stimuli, endoplasmic reticulum (ER) stress is activated and regulates apoptosis and inflammation. Excessive apoptosis promotes aortic inflammation and degeneration, leading to TAAD. Therefore, we studied the role of ER stress in TAAD formation. A lysyl oxidase inhibitor, 3-aminopropionitrile fumarate (BAPN), was administrated to induce TAAD formation in mice, which showed significant SMC loss (α-SMA level). Excessive apoptosis (TUNEL staining) and ER stress (ATF4 and CHOP), along with inflammation, were present in TAAD samples from both mouse and human. Transcriptional profiling of SMCs after mechanical stress demonstrated the expression of genes for ER stress and inflammation. To explore the causal role of ER stress in initiating degenerative signalling events and TAAD, we treated wild-type (CHOP(+/+)) or CHOP(-/-) mice with BAPN and found that CHOP deficiency protected against TAAD formation and rupture, as well as reduction in α-SMA level. Both SMC apoptosis and inflammation were significantly reduced in CHOP(-/-) mice. Moreover, SMCs isolated from CHOP(-/-) mice were resistant to mechanical stress-induced apoptosis. Taken together, our results demonstrated that mechanical stress-induced ER stress promotes SMCs apoptosis, inflammation and degeneration, providing insight into TAAD formation and progression.
authors: Beijing Anzhen Hospital, Capital Medical University, Key Laboratory of Remodelling-related Cardiovascular Diseases, Ministry of Education, Beijing Collaborative Innovation Centre for Cardiovascular Disorders, Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing, People's Republic of China.
authors: Li-Xin
authors: LX
authors: Jia
authors: Beijing Anzhen Hospital, Capital Medical University, Key Laboratory of Remodelling-related Cardiovascular Diseases, Ministry of Education, Beijing Collaborative Innovation Centre for Cardiovascular Disorders, Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing, People's Republic of China.
authors: Wen-Mei
authors: WM
authors: Zhang
authors: Beijing Anzhen Hospital, Capital Medical University, Key Laboratory of Remodelling-related Cardiovascular Diseases, Ministry of Education, Beijing Collaborative Innovation Centre for Cardiovascular Disorders, Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing, People's Republic of China.
authors: Hong-Jia
authors: HJ
authors: Zhang
authors: Beijing Anzhen Hospital, Capital Medical University, Key Laboratory of Remodelling-related Cardiovascular Diseases, Ministry of Education, Beijing Collaborative Innovation Centre for Cardiovascular Disorders, Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing, People's Republic of China.
authors: Tao-Tao
authors: TT
authors: Li
authors: Beijing Anzhen Hospital, Capital Medical University, Key Laboratory of Remodelling-related Cardiovascular Diseases, Ministry of Education, Beijing Collaborative Innovation Centre for Cardiovascular Disorders, Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing, People's Republic of China.
authors: Yue-Li
authors: YL
authors: Wang
authors: Beijing Anzhen Hospital, Capital Medical University, Key Laboratory of Remodelling-related Cardiovascular Diseases, Ministry of Education, Beijing Collaborative Innovation Centre for Cardiovascular Disorders, Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing, People's Republic of China.
authors: Yan-Wen
authors: YW
authors: Qin
authors: Beijing Anzhen Hospital, Capital Medical University, Key Laboratory of Remodelling-related Cardiovascular Diseases, Ministry of Education, Beijing Collaborative Innovation Centre for Cardiovascular Disorders, Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing, People's Republic of China.
authors: Hong
authors: H
authors: Gu
authors: Beijing Anzhen Hospital, Capital Medical University, Key Laboratory of Remodelling-related Cardiovascular Diseases, Ministry of Education, Beijing Collaborative Innovation Centre for Cardiovascular Disorders, Beijing Institute of Heart, Lung and Blood Vessel Disease, Beijing, People's Republic of China.
authors: Jie
authors: J
authors: Du
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000629:Aminopropionitrile / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000378:metabolism; D017545:Aortic Aneurysm, Thoracic / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D017209:Apoptosis; D002478:Cells, Cultured; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D007249:Inflammation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D015398:Signal Transduction; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism
chemical_list: C497109:ATF4 protein, human; C081452:Atf4 protein, mouse; C497249:DDIT3 protein, human; C497250:Ddit3 protein, mouse; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D000629:Aminopropionitrile
keywords: CHOP; ER stress; SMCs; apoptosis; thoracic aortic aneurysm/dissection