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

Abstract

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.