The Interplay of Mitochondrial Oxidative Stress and Endoplasmic Reticulum Stress in Cardiovascular Fibrosis in Obese Rats

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.

Oxidative Stress Can Be Attenuated by 4-PBA Caused by High-Fat or Ammonia Nitrogen in Cultured Spotted Seabass: The Mechanism Is Related to Endoplasmic Reticulum Stress

“…The overexpression of UPR components, such as CHOP and ATF4, directly contribute to ROS synthesis in the ER [ 33 ]. Moreover, the impaired ER can translate Ca 2+ to mitochondria through the calcium release channel and mitochondrial-associated membranes, which exaggerates the production of ROS via the electron transport chain (ETC) [ 46 ]. In the present study, the expression of CHOP and ATF4 were downregulated by dietary 4-PBA.…”

Drug Resistance and Endoplasmic Reticulum Stress in Hepatocellular Carcinoma

“…In an effort to further examine the influence of Nrf2 on cell death, another study suggests that its elicitation might be related to mitochondrial DNA depletion in HCC cell lines [ 89 ]. It has been previously demonstrated that there is an underlying relationship between mtDNA and ER stress, suggesting that any disturbance in the ER could have an impact on mtDNA and vice versa [ 90 , 91 , 92 ]. Investigating the crosstalk between ER stress and mtDNA depletion could then provide precious insights to further assess chemoresistance mechanisms in HCC in relation to cell death [ 92 ], especially as mtDNA depletion was also found to trigger other markers such as survivin, Bax, and Bcl2, which, when imbalanced, hinder pro-apoptotic signals [ 89 ].…”

Oxidative stress in obesity and insulin resistance

“…Significant association of antioxidant defense parameters with anthropometric, lipid, and inflammatory markers has also been shown in obese young adults with increased risk of cardiovascular diseases [69,70]. In addition, the latest advances in the field of obesity-related OxS biology are explorations regarding telomere length [71] and mitochondrial OxS [72,73]. It shows that telomeres shorten according to the length of obesity phenotype and also to the degree of OxS influenced by obesity [71].…”

“…It shows that telomeres shorten according to the length of obesity phenotype and also to the degree of OxS influenced by obesity [71]. Furthermore, recent studies show the relevance of mitochondrial OxS in metabolic alterations associated with obesity and mitochondrial OxS in the dysbiosis associated with a high-fat diet (HFD) in rats [72,73].…”