scholarly journals Oxidative Stress and New Pathogenetic Mechanisms in Endothelial Dysfunction: Potential Diagnostic Biomarkers and Therapeutic Targets

2020 ◽  
Vol 9 (6) ◽  
pp. 1995 ◽  
Author(s):  
Maria Giovanna Scioli ◽  
Gabriele Storti ◽  
Federico D’Amico ◽  
Roger Rodríguez Guzmán ◽  
Federica Centofanti ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Cytochrome C ◽  
Enzyme Inhibitors ◽  
Leukocyte Adhesion ◽  
Experimental Studies ◽  
Density Lipoprotein ◽  
Cell Permeability ◽  
Cytochrome C Release ◽  
Mortality And Morbidity

Cardiovascular diseases (CVD), including heart and pathological circulatory conditions, are the world’s leading cause of mortality and morbidity. Endothelial dysfunction involved in CVD pathogenesis is a trigger, or consequence, of oxidative stress and inflammation. Endothelial dysfunction is defined as a diminished production/availability of nitric oxide, with or without an imbalance between endothelium-derived contracting, and relaxing factors associated with a pro-inflammatory and prothrombotic status. Endothelial dysfunction-induced phenotypic changes include up-regulated expression of adhesion molecules and increased chemokine secretion, leukocyte adherence, cell permeability, low-density lipoprotein oxidation, platelet activation, and vascular smooth muscle cell proliferation and migration. Inflammation-induced oxidative stress results in an increased accumulation of reactive oxygen species (ROS), mainly derived from mitochondria. Excessive ROS production causes oxidation of macromolecules inducing cell apoptosis mediated by cytochrome-c release. Oxidation of mitochondrial cardiolipin loosens cytochrome-c binding, thus, favoring its cytosolic release and activation of the apoptotic cascade. Oxidative stress increases vascular permeability, promotes leukocyte adhesion, and induces alterations in endothelial signal transduction and redox-regulated transcription factors. Identification of new endothelial dysfunction-related oxidative stress markers represents a research goal for better prevention and therapy of CVD. New-generation therapeutic approaches based on carriers, gene therapy, cardiolipin stabilizer, and enzyme inhibitors have proved useful in clinical practice to counteract endothelial dysfunction. Experimental studies are in continuous development to discover new personalized treatments. Gene regulatory mechanisms, implicated in endothelial dysfunction, represent potential new targets for developing drugs able to prevent and counteract CVD-related endothelial dysfunction. Nevertheless, many challenges remain to overcome before these technologies and personalized therapeutic strategies can be used in CVD management.

Abstract 371: Mitochondrial Antiviral Signaling (MAVS) Protects Cardiomyocytes Under Oxidative Stress by Interfering with Bax-Mediated Cell Death

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Toshitaka Yajima ◽  
Stanley Park ◽  
Hanbing Zhou ◽  
Michinari Nakamura ◽  
Mitsuyo Machida ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Membrane Potential ◽  
Cytochrome C ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Cytochrome C Release ◽  
Antiviral Signaling ◽  
Cell Death Pathway ◽  
The Impact

MAVS is a mitochondrial outer membrane protein that activates innate antiviral signaling by recognizing cytosolic viral RNAs and DNAs. While the discovery of MAVS is the first molecular evidence that links mitochondria to innate immune mechanisms, it is still unclear whether MAVS affects mitochondrial cell death as a member of caspase activation and recruitment domain (CARD)-containing proteins. We found that MAVS interacts with Bax through CARD by Yeast two-hybrid and a series of immunoprecipitation (IP) assay, which led us to hypothesize that MAVS functions not only in the innate antiviral mechanisms but also in the mitochondrial cell death pathway. Methods: 1) We examined molecular interaction between MAVS and Bax under oxidative stress by IP using isolated myocytes with H2O2 stimulation and the heart post ischemia-reperfusion (I/R). 2) We evaluated the effect of MAVS on mitochondrial membrane potential and apoptosis under H2O2 stimulation using isolated myocytes with adenoviral MAVS knockdown. 3) We investigated the impact of MAVS on %myocardial infarction (%MI) post I/R using cardiac-specific MAVS knockout (cKO) and transgenic (cTg) mice which we have originally generated. 4) We examined the effect of MAVS on recombinant Bax (rBax)-mediated cytochrome c release using isolated mitochondria from wild type (WT) and MAVS KO mice. Results: 1) The amount of Bax pulled down with MAVS was significantly increased in isolated myocytes with 0.2 mM H2O2 compared to those without stimulation (mean±SD; 1.808±0.14, n=5, p<0.001) and in the heart post I/R compared to sham (2.2±1.19, n=3, p=0.0081). 2) Myocytes with MAVS knockdown showed clear abnormalities in mitochondrial membrane potential and caspace-3 cleavage with 0.2 mM H2O2 compared to control cardiomyocytes. 3) MAVS cKO had significantly larger %MI than WT (81.9 ± 5.8% vs. 42.6 ± 13.6%, n=8, p=0.0008). In contrast, MAVS cTg had significantly smaller %MI that WT (30.0 ± 4.8% vs. 49.2 ± 4.8%, n=10, p=0.0113). 4) Mitochondria from MAVS KO exhibited cytochrome c release after incubation with 2.5 μ g of rBax while those from WT required 10 μ g of rBax. Conclusion: These results demonstrate that MAVS protects cardiomyocyte under oxidative stress by interfering with Bax-mediated cytochrome c release from mitochondria.

scholarly journals miR-21-mediated decreased neutrophil apoptosis is a determinant of impaired coronary collateral growth in metabolic syndrome

2015 ◽  
Vol 308 (11) ◽  
pp. H1323-H1335 ◽  
Author(s):  
Rebecca Hutcheson ◽  
Russell Terry ◽  
Brenda Hutcheson ◽  
Rashmi Jadhav ◽  
Jennifer Chaplin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Metabolic Syndrome ◽  
Cytochrome C ◽  
Stress Generation ◽  
Neutrophil Apoptosis ◽  
Cytochrome C Release ◽  
Coronary Collateral ◽  
Sd Rats ◽  
Collateral Growth ◽  
Coronary Collateral Growth

Coronary collateral growth (CCG) is impaired in metabolic syndrome. microRNA-21 (miR-21) is a proproliferative and antiapoptotic miR, which we showed to be elevated in metabolic syndrome. Here we investigate whether impaired CCG in metabolic syndrome involved miR-21-mediated aberrant apoptosis. Normal Sprague-Dawley (SD) and metabolic syndrome [J. C. Russel (JCR)] rats underwent transient, repetitive coronary artery occlusion [repetitive ischemia (RI)]. Antiapoptotic Bcl-2, phospho-Bad, and Bcl-2/Bax dimers were increased on days 6 and 9 RI, and proapoptotic Bax and Bax/Bax dimers and cytochrome- c release concurrently decreased in JCR versus SD rats. Active caspases were decreased in JCR versus SD rats (∼50%). Neutrophils increased transiently on day 3 RI in the collateral-dependent zone of SD rats but remained elevated in JCR rats, paralleling miR-21 expression. miR-21 downregulation by anti-miR-21 induced neutrophil apoptosis and decreased Bcl-2 and Bcl-2/Bax dimers (∼75%) while increasing Bax/Bax dimers, cytochrome- c release, and caspase activation (∼70, 400, and 400%). Anti-miR-21 also improved CCG in JCR rats (∼60%). Preventing neutrophil infiltration with blocking antibodies resulted in equivalent CCG recovery, confirming a major role for deregulated neutrophil apoptosis in CCG impairment. Neutrophil and miR-21-dependent CCG inhibition was in significant part mediated by increased oxidative stress. We conclude that neutrophil apoptosis is integral to normal CCG and that inappropriate prolonged miR-21-mediated survival of neutrophils plays a major role in impaired CCG, in part via oxidative stress generation.

scholarly journals Mitochondria, oxidative stress, and antioxidant defences.

1999 ◽  
Vol 46 (1) ◽  
pp. 1-21 ◽  
Author(s):  
G Lenaz ◽  
C Bovina ◽  
G Formiggini ◽  
G Parenti Castelli
Keyword(s):  
Oxidative Stress ◽  
Cytochrome C ◽  
Coenzyme Q ◽  
Lactate Production ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Human Platelets ◽  
Cytochrome C Release ◽  
Antioxidant Defences

Mitochondria are strongly involved in production of reactive oxygen species, considered today as the main pathogenic agent of many diseases. A vicious circle of oxidative stress and damage to cellular structures can lead to either cell death by apoptosis or to a cellular energetic decline and ageing. The early involvement of mitochondria in apoptosis includes expression of pro-apoptotic factors, release of cytochrome c from the inter-membrane space and opening of the permeability transition pore: cytochrome c release appears to precede pore opening. The mitochondrial theory of ageing considers somatic mutations (deletions) of mitochondrial DNA induced by oxygen radicals as the primary cause of energy decline; experimentally, Complex I appears to be mostly affected. We have developed the Pasteur effect (enhancement of lactate production by mitochondrial inhibition) as a bio-marker of mitochondrial bioenergetics in human platelets, and found it to be decreased in aged individuals. Cells counteract oxidative stress by antioxidants; among lipophilic antioxidants coenzyme Q is the only one of endogenous biosynthesis; exogenous coenzyme Q, however, may protect cells from oxidative stress in vivo.

scholarly journals Resveratrol Attenuates Oxidized LDL-Evoked Lox-1 Signaling and Consequently Protects against Apoptotic Insults to Cerebrovascular Endothelial Cells

2010 ◽  
Vol 31 (3) ◽  
pp. 842-854 ◽  
Author(s):  
Huai-Chia Chang ◽  
Tyng-Guey Chen ◽  
Yu-Ting Tai ◽  
Ta-Liang Chen ◽  
Wen-Ta Chiu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cytochrome C ◽  
Dna Fragmentation ◽  
Cell Apoptosis ◽  
Molecular Mechanisms ◽  
Cell Damage ◽  
Oxidized Ldl ◽  
Density Lipoprotein ◽  
Cytochrome C Release ◽  
Cerebrovascular Endothelial Cells

Cerebrovascular endothelial cells (CECs) are crucial components of the blood—brain barrier. Our previous study showed that oxidized low-density lipoprotein (oxLDL) induces apoptosis of CECs. This study was designed to further evaluate the effects of resveratrol on oxLDL-induced CEC insults and its possible molecular mechanisms. Resveratrol decreased the oxidation of LDL into oxLDL. Additionally, the oxLDL-caused oxidative stress and cell damage were attenuated by resveratrol. Exposure of CECs to oxLDL induced cell shrinkage, DNA fragmentation, and cell apoptosis, but resveratrol defended against such injuries. Application of Lox-1 small interference (si)RNA into CECs reduced the translation of this membrane receptor, and simultaneously increased resveratrol protection from oxLDL-induced cell apoptosis. By comparison, overexpression of Lox-1 attenuated resveratrol protection. Resveratrol inhibited oxLDL-induced Lox-1 mRNA and protein expressions. Both resveratrol and Lox-1 siRNA decreased oxLDL-enhanced translocation of proapoptotic Bcl-2-associated X protein (Bax) from the cytoplasm to mitochondria. Sequentially, oxLDL-induced alterations in the mitochondrial membrane potential, cytochrome c release, and activities of caspases-9, -3, and -6 were decreased by resveratrol. Pretreatment with Z-VEID-FMK (benzyloxycarbonyl-Leu-Glu-His-Asp-fluoromethyl ketone) synergistically promoted resveratrol's protection against DNA fragmentation and cell apoptosis. Therefore, this study shows that resveratrol can protect CECs from oxLDL-induced apoptotic insults via downregulating Lox-1-mediated activation of the Bax-mitochondria—cytochrome c—caspase protease pathway.

Glycyrrhizic acid renders robust neuroprotection in rodent model of vascular dementia by controlling oxidative stress and curtailing cytochrome-c release

2019 ◽  
Vol 23 (12) ◽  
pp. 955-970 ◽  
Author(s):  
Yogeshkanna Sathyamoorthy ◽  
Kathiravan Kaliappan ◽  
Pradeepkumar Nambi ◽  
Rameshkumar Radhakrishnan
Keyword(s):  
Oxidative Stress ◽  
Cytochrome C ◽  
Vascular Dementia ◽  
Glycyrrhizic Acid ◽  
Rodent Model ◽  
Cytochrome C Release

Mechanistic view for toxic effects of arsenic on isolated rat kidney and brain mitochondria

Biologia ◽  
2015 ◽  
Vol 70 (5) ◽  
Author(s):  
Shokoufeh Hassani ◽  
Hashem Yaghoubi ◽  
Roya Khosrokhavar ◽  
Iman Jafarian ◽  
Vida Mashayekhi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cytochrome C ◽  
Outer Membrane ◽  
Brain Mitochondria ◽  
Male Rats ◽  
Arsenic Toxicity ◽  
Cytochrome C Release ◽  
Oxidation Stress ◽  
Complex Ii ◽  
Ros Formation

AbstractArsenic is one of the most important risk factors for human health and exhibits carcinogenicity in human. Emerging lines of research indicate that mitochondria are important target organelles for metals toxicity in living cells. In this study male rats were sacrificed and then kidney and brain mitochondria were isolated using ultracentrifugation method. Then, multi-parametric assays including reactive oxygen species (ROS) formation, complex II and IV activity, outer membrane integrity, ATP level and release of cytochrome c release evaluated to predict the biochemical pathways involved in arsenic toxicity. Our results showed that arsenic (25-200 μM) induced significant ROS formation rise and mitochondrial outer membrane damage in kidney and brain mitochondria, mitochondrial membrane potential collapse and mitochondrial ATP levels. Significant decrease in the complex II and IV activity in brain without any change in kidney mitochondria suggests the inevitable role of oxidative stress in mitochondrial permeability transition-mediated cytochrome c release. Therefore, it is supposed that mitochondrial oxidative stress and uncoupling of oxidative phosphorylation may play key roles in arsenic toxicity towards isolated kidney and brain mitochondria. Also, comparison of present study with previous investigations supposed that liver is more susceptible to arsenic exposure and induction of oxidation stress-like condition than kidney and brain tissues.

Attenuation of oxidative stress, inflammation, and endothelial dysfunction in hypercholesterolemic rabbits by allicin

2016 ◽  
Vol 94 (2) ◽  
pp. 216-224 ◽  
Author(s):  
Ahmed R. El-Sheakh ◽  
Hamdy A. Ghoneim ◽  
Ghada M. Suddek ◽  
El Sayed M. Ammar
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Immunohistochemical Staining ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
High Cholesterol Diet ◽  
Chow Diet ◽  
Beneficial Effects ◽  
Aortic Pathology ◽  
Tnf Α

Allicin, the active substance of garlic, exerts a broad spectrum of pharmacological activities and is considered to have potential therapeutic applications. The present study was designed to investigate the possible beneficial effects of allicin against oxidative stress, inflammation, and endothelial dysfunction in hypercholesterolemic rabbits. Male New Zealand white rabbits were used in this study. Rabbits randomly received 1 of the following treatments: normal chow diet for 4 weeks, 1% high cholesterol diet (HCD), HCD plus allicin (10 mg/kg/day), or HCD plus atorvastatin (10 mg/kg/day). Blood samples were collected at the end of experimental diets for measurement of serum total cholesterol (TC), triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C), C-reactive protein (CRP), malondialdehyde (MDA), reduced glutathione (GSH), and superoxide dismutase (SOD). In addition, the aorta was removed for measurement of vascular reactivity, histopathological changes, intima/media (I/M) ratio, and immunohistochemical staining of both tumor necrosis-alpha (TNF-α) and nuclear factor (NF)-κB. HCD induced significant increases in serum TC, TGs, low-density lipoprotein cholesterol (LDL-C), CRP, and MDA. Moreover, HCD caused significant decrease in serum GSH and SOD. In addition, aortic relaxation response to acetylcholine (ACh) was impaired. Immunohistochemical staining of aortic specimens from HCD-fed rabbits revealed high expression levels of both TNF-α and the oxidant-induced transcription factor, NF-κB. Allicin supplementation significantly decreased serum MDA and CRP, increased serum HDL-C, GSH, and SOD levels while nonsignificantly affecting HCD-induced elevations in serum TC and LDL-C. Additionally, allicin significantly protected against HCD-induced attenuation of rabbit aortic endothelium-dependent relaxation to ACh and elevation in I/M ratio. This effect was confirmed by histopathological examination of the aorta. Moreover, allicin has substantially beneficial effects on aortic expression of TNF-α and NF-κB compared with HCD-fed rabbits. In conclusion, these findings demonstrate that allicin may be useful in reducing oxidative stress, inflammation, vascular dysfunction, and the aortic pathology in hypercholesterolemic rabbits.

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