scholarly journals Mitochondria-Targeted Antioxidant Prevents Cardiac Dysfunction Induced by Tafazzin Gene Knockdown in Cardiac Myocytes

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Quan He ◽  
Nicole Harris ◽  
Jun Ren ◽  
Xianlin Han
Keyword(s):  
Cardiac Myocytes ◽  
Cardiac Dysfunction ◽  
Barth Syndrome ◽  
Gene Knockdown ◽  
Side Chain ◽  
Ros Production ◽  
Mitochondrial Oxidative Stress ◽  
Mitochondrial Ros ◽  
Steady State Levels ◽  
Tafazzin Gene

Tafazzin, a mitochondrial acyltransferase, plays an important role in cardiolipin side chain remodeling. Previous studies have shown that dysfunction of tafazzin reduces cardiolipin content, impairs mitochondrial function, and causes dilated cardiomyopathy in Barth syndrome. Reactive oxygen species (ROS) have been implicated in the development of cardiomyopathy and are also the obligated byproducts of mitochondria. We hypothesized that tafazzin knockdown increases ROS production from mitochondria, and a mitochondria-targeted antioxidant prevents tafazzin knockdown induced mitochondrial and cardiac dysfunction. We employed cardiac myocytes transduced with an adenovirus containing tafazzin shRNA as a model to investigate the effects of the mitochondrial antioxidant, mito-Tempo. Knocking down tafazzin decreased steady state levels of cardiolipin and increased mitochondrial ROS. Treatment of cardiac myocytes with mito-Tempo normalized tafazzin knockdown enhanced mitochondrial ROS production and cellular ATP decline. Mito-Tempo also significantly abrogated tafazzin knockdown induced cardiac hypertrophy, contractile dysfunction, and cell death. We conclude that mitochondria-targeted antioxidant prevents cardiac dysfunction induced by tafazzin gene knockdown in cardiac myocytes and suggest mito-Tempo as a potential therapeutic for Barth syndrome and other dilated cardiomyopathies resulting from mitochondrial oxidative stress.

Abstract 224: Mitochondrial Complex I Deficiency Promotes Oxidative Stress During Ischemia Reperfusion Of Cardiac Myocytes

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Guohua Gong ◽  
Georgios Karamanlidis ◽  
Chi Fung Lee ◽  
Rong Tian ◽  
Wang Wang
Keyword(s):  
Oxidative Stress ◽  
Cardiac Myocytes ◽  
Complex I ◽  
Ischemia Reperfusion ◽  
Mitochondrial Complex I ◽  
Ros Production ◽  
Mitochondrial Complex ◽  
Complex I Deficiency ◽  
Mitochondrial Ros ◽  
Complex I Activity

Normal cardiac function relies on highly coordinated intracellular events, such as calcium cycling and contraction, with adequate mitochondrial energy metabolism. However, mitochondrial respiration unavoidably produces reactive oxygen species (ROS) as electrons leak from the electron transport chain (ETC). Complex I of the ETC is believed to be the major site for ROS generation in the mitochondria. However, suppression of Complex I activity by chemical inhibitors leads to oxidative cell damage. In this study, we used a genetic model of Complex I deficiency, in which a key component of Complex I, Ndufs4, was deleted in the heart, to determine the causal role of Complex I in ischemia-reperfusion-induced oxidative stress in adult cardiac myocytes. Germline deletion of Ndufs4 in the heart (Ndufs4H-/-) leads to a ~75% decline of Complex I activity in cardiac mitochondria without obvious disease phenotype in the mice. As predicted, the mitochondrial respiration-coupled superoxide production events, superoxide flashes, were significantly decreased at baseline in the Ndufs4H-/- myocytes. Respiration substrate (pyruvate, 20 mM) failed to stimulate mitochondrial superoxide flash production in Ndufs4H-/- myocytes. This is accompanied by the slightly decreased steady state intracellular and mitochondrial ROS levels determined by the targeted H2O2 indicator, Hyper. The intracellular redox homeostasis is also tilted toward more reduced state, since the NADH/NAD ratio increased 67%. Surprisingly, ischemia reperfusion mimetic treatment of the myocytes caused dramatic increase in mitochondrial ROS production in Ndufs4H-/- groups, which contributed to the elevated overall cellular oxidative status. Overexpression of catalase in the mitochondria prevented these effects. Mechanistically, increased reducing equivalent (NADH) contributed to the dramatic ROS production during ischemia and reperfusion in Ndufs4H-/- myocytes. In summary, mitochondrial Complex I plays a critical role in controlling mitochondrial and cytosolic ROS homeostasis under normal conditions, and compromised Complex I function leads to accumulation of electron donors that paradoxically promote ROS production during ischemia reperfusion.

1703-P: Altered UCP1 Expression in ADSC-Derived Beige Adipocytes Determines Mitochondrial ROS Production in T2DM Patients

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 1703-P
Author(s):  
SVETLANA MICHURINA ◽  
IURII STAFEEV ◽  
IGOR SKLYANIK ◽  
EKATERINA SHESTAKOVA ◽  
ANATOLIY YURASOV ◽  
...  
Keyword(s):  
Ros Production ◽  
Mitochondrial Ros ◽  
Beige Adipocytes ◽  
Ucp1 Expression

scholarly journals Lycopene Inhibits Toll-Like Receptor 4-Mediated Expression of Inflammatory Cytokines in House Dust Mite-Stimulated Respiratory Epithelial Cells

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3127
Author(s):  
Jiyeon Choi ◽  
Joo Weon Lim ◽  
Hyeyoung Kim
Keyword(s):  
Epithelial Cells ◽  
A549 Cells ◽  
Cytokine Expression ◽  
Ros Production ◽  
Toll Like Receptor ◽  
Respiratory Epithelial Cells ◽  
Toll Like Receptor 4 ◽  
Mitochondrial Ros ◽  
Tlr4 Activation ◽  
Respiratory Epithelial

House dust mites (HDM) are critical factors in airway inflammation. They activate respiratory epithelial cells to produce reactive oxygen species (ROS) and activate Toll-like receptor 4 (TLR4). ROS induce the expression of inflammatory cytokines in respiratory epithelial cells. Lycopene is a potent antioxidant nutrient with anti-inflammatory activity. The present study aimed to investigate whether HDM induce intracellular and mitochondrial ROS production, TLR4 activation, and pro-inflammatory cytokine expression (IL-6 and IL-8) in respiratory epithelial A549 cells. Additionally, we examined whether lycopene inhibits HDM-induced alterations in A549 cells. The treatment of A549 cells with HDM activated TLR4, induced the expression of IL-6 and IL-8, and increased intracellular and mitochondrial ROS levels. TAK242, a TLR4 inhibitor, suppressed both HDM-induced ROS production and cytokine expression. Furthermore, lycopene inhibited the HDM-induced TLR4 activation and cytokine expression, along with reducing the intracellular and mitochondrial ROS levels in HDM-treated cells. These results collectively indicated that the HDM induced TLR4 activation and increased intracellular and mitochondrial ROS levels, thus resulting in the induction of cytokine expression in respiratory epithelial cells. The antioxidant lycopene could inhibit HDM-induced cytokine expression, possibly by suppressing TLR4 activation and reducing the intracellular and mitochondrial ROS levels in respiratory epithelial cells.

scholarly journals Mitochondrial depolarization underlies delay in permeability transition by preconditioning with isoflurane: roles of ROS and Ca2+

2010 ◽  
Vol 299 (2) ◽  
pp. C506-C515 ◽  
Author(s):  
Filip Sedlic ◽  
Ana Sepac ◽  
Danijel Pravdic ◽  
Amadou K. S. Camara ◽  
Martin Bienengraeber ◽  
...  
Keyword(s):  
Cell Survival ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Underlying Mechanism ◽  
Ros Production ◽  
Trypan Blue Exclusion ◽  
Mptp Opening ◽  
Mitochondrial Ros ◽  
Cardioprotective Effects

During reperfusion, the interplay between excess reactive oxygen species (ROS) production, mitochondrial Ca2+ overload, and mitochondrial permeability transition pore (mPTP) opening, as the crucial mechanism of cardiomyocyte injury, remains intriguing. Here, we investigated whether an induction of a partial decrease in mitochondrial membrane potential (ΔΨm) is an underlying mechanism of protection by anesthetic-induced preconditioning (APC) with isoflurane, specifically addressing the interplay between ROS, Ca2+, and mPTP opening. The magnitude of APC-induced decrease in ΔΨm was mimicked with the protonophore 2,4-dinitrophenol (DNP), and the addition of pyruvate was used to reverse APC- and DNP-induced decrease in ΔΨm. In cardiomyocytes, ΔΨm, ROS, mPTP opening, and cytosolic and mitochondrial Ca2+ were measured using confocal microscope, and cardiomyocyte survival was assessed by Trypan blue exclusion. In isolated cardiac mitochondria, antimycin A-induced ROS production and Ca2+ uptake were determined spectrofluorometrically. In cells exposed to oxidative stress, APC and DNP increased cell survival, delayed mPTP opening, and attenuated ROS production, which was reversed by mitochondrial repolarization with pyruvate. In isolated mitochondria, depolarization by APC and DNP attenuated ROS production, but not Ca2+ uptake. However, in stressed cardiomyocytes, a similar decrease in ΔΨm attenuated both cytosolic and mitochondrial Ca2+ accumulation. In conclusion, a partial decrease in ΔΨm underlies cardioprotective effects of APC by attenuating excess ROS production, resulting in a delay in mPTP opening and an increase in cell survival. Such decrease in ΔΨm primarily attenuates mitochondrial ROS production, with consequential decrease in mitochondrial Ca2+ uptake.

Alteration in the expression of genes for cholesterol side-chain cleavage enzyme and 21-hydroxylase by hypophysectomy and ACTH administration in the rat adrenal

1990 ◽  
Vol 4 (3) ◽  
pp. 239-245 ◽  
Author(s):  
T. Imai ◽  
H. Seo ◽  
Y. Murata ◽  
M. Ohno ◽  
Y. Satoh ◽  
...  
Keyword(s):  
Steady State ◽  
Adrenal Weight ◽  
Side Chain ◽  
Total Rna ◽  
Side Chain Cleavage ◽  
Chain Cleavage ◽  
Acth Treatment ◽  
Steady State Levels ◽  
Cytochrome P 450

ABSTRACT The changes in steady-state levels of mRNA for cholesterol side-chain cleavage cytochrome P-450 (P-450scc) and steroid 21-hydroxylase cytochrome P-450 (P-450c21) caused by hypophysectomy and ACTH treatment were determined in rat adrenals. Hypophysectomy caused marked decreases in adrenal weight and total RNA per gland. Administration of ACTH resulted in increases in adrenal weight and total RNA. A significant correlation between the amount of RNA and adrenal weight was observed. Both P-450scc and P-450c21 mRNAs were decreased by hypophysectomy and increased by ACTH treatment. P-450scc mRNA decreased to 20% and P-450c21 mRNA to 76% of control values 1 day after hypophysectomy. ACTH caused a significant increase in P-450scc mRNA after 3 h. However, a significant increase in P-450c21 mRNA was observed 12 h after administration of ACTH. These results are concordant with previous studies in vitro utilizing cultured adrenocortical cells. Moreover, the induction of steady-state levels of P-450scc mRNA was faster than that observed by other investigators in studies in vitro. These results may indicate that integrity of the adrenal gland in vivo is important for the action of ACTH.

scholarly journals HIV-1 Tat protein induces DNA damage in human peripheral blood B-lymphocytes via mitochondrial ROS production

Redox Biology ◽  
2018 ◽  
Vol 15 ◽  
pp. 97-108 ◽  
Author(s):  
Rawan El-Amine ◽  
Diego Germini ◽  
Vlada V. Zakharova ◽  
Tatyana Tsfasman ◽  
Eugene V. Sheval ◽  
...  
Keyword(s):  
Dna Damage ◽  
B Lymphocytes ◽  
Peripheral Blood ◽  
Human Peripheral Blood ◽  
Ros Production ◽  
Tat Protein ◽  
Mitochondrial Ros ◽  
Hiv 1

scholarly journals TNFR1 and TNFR2 Signaling Interplay in Cardiac Myocytes

2007 ◽  
Vol 282 (49) ◽  
pp. 35564-35573 ◽  
Author(s):  
Nicole Defer ◽  
Anie Azroyan ◽  
Françoise Pecker ◽  
Catherine Pavoine
Keyword(s):  
Cardiac Myocytes ◽  
Protective Role ◽  
Limiting Factor ◽  
Receptor Subtypes ◽  
Ros Production ◽  
Altered Cell ◽  
Factor Α ◽  
Positive Effect ◽  
Fractional Shortening

Tumor necrosis factor α (TNFα) plays a major role in chronic heart failure, signaling through two different receptor subtypes, TNFR1 and TNFR2. Our aim was to further delineate the functional role and signaling pathways related to TNFR1 and TNFR2 in cardiac myocytes. In cardiac myocytes isolated from control rats, TNFα induced ROS production, exerted a dual positive and negative action on [Ca2+] transient and cell fractional shortening, and altered cell survival. Neutralizing anti-TNFR2 antibodies exacerbated TNFα responses on ROS production and cell death, arguing for a major protective role of the TNFR2 pathway. Treatment with either neutralizing anti-TNFR1 antibodies or the glutathione precursor, N-acetylcysteine (NAC), favored the emergence of TNFR2 signaling that mediated a positive effect of TNFα on [Ca2+] transient and cell fractional shortening. The positive effect of TNFα relied on TNFR2-dependent activation of the cPLA2 activity, independently of serine 505 phosphorylation of the enzyme. Together with cPLA2 redistribution and AA release, TNFα induced a time-dependent phosphorylation of ERK, MSK1, PKCζ, CaMKII, and phospholamban on the threonine 17 residue. Taken together, our results characterized a TNFR2-dependent signaling and illustrated the close interplay between TNFR1 and TNFR2 pathways in cardiac myocytes. Although apparently predominant, TNFR1-dependent responses were under the yoke of TNFR2, acting as a critical limiting factor. In vivo NAC treatment proved to be a unique tool to selectively neutralize TNFR1-mediated effects of TNFα while releasing TNFR2 pathways.

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