Inhibition of endoplasmic reticulum stress and mitochondrial oxidative
stress limits the development of abdominal aortic aneurysm and cardiac
hypertrophy
Abstract
Background and purpose: Persistent endoplasmic reticulum (ER) stress and
its deleterious crosstalk with mitochondria trigger oxidative stress,
mitochondrial dysfunction and inflammation contributing to the
pathophysiology of a myriad of cardiovascular diseases linked with
hypertension such as abdominal aortic aneurysm (AAA) and cardiac
hypertrophy. The purpose of this work was to determine whether
inhibition of ER and mitochondrial stress is effective preventing
aneurysm development and cardiac hypertrophy in angiotensin II
(AngII)-infused apolipoprotein-E-deficient (ApoE−/−) mice. Experimental
approach and results: The expression of ER stress markers (Hspa5, Atf4,
Atf6, Chop and Ern1) was up-regulated in aneurysmal abdominal aortas
from AngII-infused ApoE−/−mice. The treatment with ER stress inhibitors
improved survival, decreased systolic blood pressure, limited the
incidence and severity of AAA and reduced the AngII-induced increase of
aortic diameter evaluated by ultrasonography. These beneficial effects
were mimicked by the mitochondria-targeted tetrapeptide SS31. The
disorganisation of elastin and collagen fibres, 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, ER inhibitors and SS31. Additionally, treatment with
SS31 prevented the alteration of mitochondrial dysfunction and reduced
ER stress markers expression and plasmatic ROS levels. Mechanistically,
CHOP deficiency in ApoE−/−mice reduced the blood pressure and the
incidence of AAA. Interestingly, both pharmacological interventions and
CHOP deficiency attenuated AngII-induced cardiac hypertrophic
remodelling and improved systolic and diastolic function. Conclusions:
Our data evidence that inhibition of ER and mitochondrial stress limits
abdominal aortic aneurysm formation, increases survival and ameliorates
hypertensive cardiac hypertrophy.