Targeting mitochondrial stress with SS31 prevents experimental abdominal aortic aneurysm: crosstalk with ER stress

by Selleckchem | Apr 19 2023

Background and purpose mitochondrial dysfunction and inflammation contribute to the pathophysiology of a myriad of cardiovascular diseases. Additionally, the deleterious crosstalk of mitochondria and persistent endoplasmic reticulum (ER) stress triggers oxidative stress, which is deeply involved in the development of vascular diseases. The purpose of this work was to determine whether 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 and results the mitochondria-targeted tetrapeptide SS31 ameliorated mitochondrial dysfunction and the enhanced expression of ER stress markers triggered by Ang II in ApoE-/- mice and limited plasmatic and vascular ROS levels. Interestingly, SS31 improved survival, reduced the incidence and severity of abdominal aortic aneurysm (AAA) and the AngII-induced increase of aortic diameter evaluated by ultrasonography, resembling the response triggered by the classic ER stress inhibitors TUDCA and PBA. The disorganization of extracellular matrix, the increased expression of metalloproteinases and pro-inflammatory markers and the infiltration of immune cells induced by AngII in the abdominal aorta were effectively reduced by both, SS31 and ER inhibitors. Further, CHOP deficiency in ApoE-/- mice attenuated the AngII-mediated increase in vascular diameter and the incidence of AAA, suggesting its contribution to the favorable response induced by ER stress inhibition. CONCLUSIONS: our data demonstrate that inhibition of mitochondrial stress by SS31 limits AAA formation and increases survival through a reduction of vascular remodeling, inflammation and ROS, and support that the attenuation of ER stress also contribute to the favorable response elicited by SS31.

Comments：

The purpose of this study was to investigate whether inhibition of mitochondrial stress could reduce aneurysm development in Angiotensin II (Ang II)-infused Apolipoprotein-E-deficient (ApoE-/-) mice and its effect on endoplasmic reticulum (ER) stress. The study found that the mitochondria-targeted tetrapeptide 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. The study also found that SS31 improved survival, reduced the incidence and severity of abdominal aortic aneurysm (AAA), and the Ang II-induced increase of aortic diameter evaluated by ultrasonography, resembling the response triggered by the classic ER stress inhibitors TUDCA and PBA.

The disorganization of extracellular matrix, the increased expression of metalloproteinases and pro-inflammatory markers, and the infiltration of immune cells induced by Ang II in the abdominal aorta were effectively reduced by both SS31 and ER inhibitors. Further, CHOP deficiency in ApoE-/- mice attenuated the Ang II-mediated increase in vascular diameter and the incidence of AAA, suggesting its contribution to the favorable response induced by ER stress inhibition.

Overall, the study demonstrates that inhibition of mitochondrial stress by SS31 limits AAA formation and increases survival through a reduction of vascular remodeling, inflammation, and ROS, and also supports the idea that the attenuation of ER stress also contributes to the favorable response elicited by SS31. These findings suggest that targeting both mitochondrial and ER stress could be a promising therapeutic approach for the prevention and treatment of cardiovascular diseases.