Targeting mitochondrial stress with Szeto‐Schiller 31 prevents experimental abdominal aortic aneurysm: Crosstalk with endoplasmic reticulum stress

• Published in: British journal of pharmacology 2023-09, Vol.180 (17), p.2230-2249
• Main Authors: Navas‐Madroñal, Miquel, Almendra‐Pegueros, Rafael, Puertas‐Umbert, Lidia, Jiménez‐Altayó, Francesc, Julve, Josep, Pérez, Belén, Consegal‐Pérez, Marta, Kassan, Modar, Martínez‐González, José, Rodriguez, Cristina, Galán, María
• Format: Article
• Language: English
• Subjects: Abdomen; ageing; Angiotensin; Angiotensin II; antioxidants; Aorta; Aortic aneurysms; Apolipoprotein E; Apolipoproteins; Cardiovascular diseases; CCAAT/enhancer-binding protein; Endoplasmic reticulum; Extracellular matrix; hypertension; in vivo; Inflammation; Mitochondria; Oxidative stress; Phenylbutyric acid; Protein deficiency; Reactive oxygen species; small molecules; Tauroursodeoxycholic acid; translational pharmacology; Vascular diseases; vascular pharmacology
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.16077

Background and Purpose Mitochondrial dysfunction and inflammation contribute to a myriad of cardiovascular diseases. Deleterious crosstalk of mitochondria and persistent endoplasmic reticulum (ER) stress triggers oxidative stress, which is involved in the development of vascular diseases. This study determined if inhibition of mitochondrial stress reduces aneurysm development in angiotensin II (Ang II)‐infused apolipoprotein‐E‐deficient (ApoE−/−) mice and its effect on ER stress. Experimental Approach The mitochondria‐targeted tetrapeptide, Szeto‐Schiller 31 (SS31), ameliorated mitochondrial dysfunction and the enhanced expression of ER stress markers triggered by Ang II in ApoE−/− mice, and limited plasmatic and vascular reactive oxygen species (ROS) levels. Interestingly, SS31 improved survival, reduced the incidence and severity of abdominal aortic aneurysm (AAA), and the Ang II‐induced increase in aortic diameter as evaluated by ultrasonography, resembling the response triggered by the classic ER stress inhibitors tauroursodeoxycholic acid (TUDCA) and 4‐phenylbutyrate (PBA). Key Results Disorganization of the extracellular matrix, increased expression of metalloproteinases and pro‐inflammatory markers and infiltration of immune cells induced by Ang II in the abdominal aorta were effectively reduced by SS31 and ER inhibitors. Further, C/EBP homologous protein (CHOP) deficiency in ApoE−/− mice attenuated Ang II‐mediated increase in vascular diameter and incidence of AAA, suggesting its contribution to the favourable response induced by ER stress inhibition. Conclusions and Implications Our data demonstrate that inhibition of mitochondrial stress by SS31 limits AAA formation and increases survival through a reduction of vascular remodelling, inflammation and ROS, and support that attenuation of ER stress contributes to the favourable response elicited by SS31.