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Targeting mitochondrial stress with Szeto-Schiller 31 prevents experimental abdominal aortic aneurysm: Crosstalk with
Miquel Navas-Madroñal1, Rafael Almendra-Pegueros1, Lidia Puertas-Umbert1
1Institut d'Investigació Biomèdica Sant Pau (IIB Sant Pau), Barcelona, Spain.
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.
Insights
Inhibition of mitochondrial stress with SS31 peptide reduced abdominal aortic aneurysm (AAA) development in mice. This intervention also decreased vascular remodelling, inflammation, and oxidative stress, improving survival.
Area of Science:
- Cardiovascular Research
- Mitochondrial Biology
- Vascular Biology
Background:
- Mitochondrial dysfunction and endoplasmic reticulum (ER) stress are implicated in cardiovascular diseases.
- Their crosstalk promotes oxidative stress, contributing to vascular disease development.
Purpose of the Study:
- To investigate if inhibiting mitochondrial stress reduces aneurysm formation in angiotensin II-infused apolipoprotein-E-deficient mice.
- To determine the effect of mitochondrial stress inhibition on ER stress.
Main Methods:
- Mice lacking apolipoprotein E (ApoE-/-) were infused with angiotensin II.
- Mice were treated with Szeto-Schiller 31 (SS31), an ER stress inhibitor, or vehicle.
- Vascular diameter, AAA incidence/severity, survival, and molecular markers were assessed.
Main Results:
- SS31 treatment ameliorated mitochondrial dysfunction and ER stress markers.
- SS31 reduced plasma and vascular reactive oxygen species (ROS) levels.
- SS31 improved survival, reduced AAA incidence/severity, and aortic diameter increase.
Conclusions:
- Inhibition of mitochondrial stress by SS31 limits AAA formation and enhances survival.
- SS31 reduces vascular remodelling, inflammation, and ROS.
- Attenuation of ER stress contributes to the protective effects of SS31.
