Abstract
We have evaluated the role of mitochondrial oxidative stress and its association with endoplasmic reticulum (ER) stress activation in the progression of obesity-related cardiovascular fibrosis. MitoQ (200 µM) was orally administered for 7 weeks to male Wistar rats that were fed a high-fat diet (HFD, 35% fat) or a control diet (CT, 3.5% fat). Obese animals presented cardiovascular fibrosis accompanied by increased levels of extracellular matrix proteins and profibrotic mediators. These alterations were associated with ER stress activation characterized by enhanced levels (in heart and aorta vs. CT group, respectively) of immunoglobulin binding protein (BiP; 2.1-and 2.6-fold, respectively), protein disulfide-isomerase A6 (PDIA6; 1.9-fold) and CCAAT-enhancer-binding homologous protein (CHOP; 1.5- and 1.8-fold, respectively). MitoQ treatment was able to prevent (p < 0.05) these modifications at cardiac and aortic levels. MitoQ (5 nM) and the ER stress inhibitor, 4-phenyl butyric acid (4 µM), were able to block the prooxidant and profibrotic effects of angiotensin II (Ang II, 10−6 M) in cardiac and vascular cells. Therefore, the data show a crosstalk between mitochondrial oxidative stress and ER stress activation, which mediates the development of cardiovascular fibrosis in the context of obesity and in which Ang II can play a relevant role.
Highlights
Cardiovascular fibrosis is a common feature in the context of obesity that occurs due to the imbalance between production and degradation of extracellular matrix components (ECM), mainly collagen type I [1]
We have demonstrated the relevance of oxidative stress in all of these alterations, since treatment with a mitochondrial antioxidant was able to prevent insulin resistance and cardiac fibrosis observed in obese animals
Stress, which is activated the cardiovascular in emerges obesity, present study, stress, which is activated in theincardiovascular system system in obesity, emerges as a potential mediator of cardiovascular fibrosis induced by mitochondrial oxias a potential mediator of cardiovascular fibrosis induced by mitochondrial oxidative stress dative stress in this context
Summary
Cardiovascular fibrosis is a common feature in the context of obesity that occurs due to the imbalance between production and degradation of extracellular matrix components (ECM), mainly collagen type I [1]. An excessive production of ROS can affect mitochondrial function and could lead to functional alterations of the heart [8,9] In this line, some data have reported the relevance of mitochondrial oxidative stress in the development of cardiac fibrosis and in the metabolic alterations in diet-induced obese rats [10,11]. Obese animals exhibited hypertrophy, interstitial fibrosis and an increase in superoxide anion levels, as compared to the reference group These modifications were prevented by treatment with the mitochondrial antioxidant, MitoQ, and were in absence of alterations in cardiac function or in blood pressure [9]. We have demonstrated the relevance of oxidative stress in all of these alterations, since treatment with a mitochondrial antioxidant was able to prevent insulin resistance and cardiac fibrosis observed in obese animals. These beneficial effects of the mitochondrial antioxidant were accompanied by a restoration in gut microbiota composition [23], showing the link between microbiota dysbiosis, oxidative stress, inflammation and cardiac alterations in the context of obesity
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