scholarly journals Mitochondrial tRNA mutation with high-salt stimulation on cardiac damage: underlying mechanism associated with change of Bax and VDAC

2016 ◽  
Vol 311 (5) ◽  
pp. H1248-H1257 ◽  
Author(s):  
Zhu Chao ◽  
Tian Liuyang ◽  
Li Nan ◽  
Chen Qi ◽  
Cai Zhongqi ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Interventricular Septum ◽  
Reactive Oxygen ◽  
Left Ventricular ◽  
High Salt ◽  
Oxygen Species ◽  
Voltage Dependent Anion Channel ◽  
Mitochondrial Trna ◽  
Cardiac Damage ◽  
Mitochondrial Transfer

Mitochondrial transfer RNA (tRNA) mutation with high-salt stimulation can cause high blood pressure. However, the underlying mechanisms remain unclear. In the present study, we examined the potential molecular mechanisms of cardiac damage caused by mitochondrial tRNA mutation with high-salt stimulation in spontaneously hypertensive rats (SHR). Unanesthetized, 44-wk-old, male, SHR were divided into four groups: SHR, SHR with high-salt stimulation for 8 wk (SHR + NaCl), SHR carrying tRNA mutations (SHR + M), and SHR + M with high-salt stimulation for 8 wk (SHR + M + NaCl). Healthy Wistar-Kyoto (WKY) rats were used as controls. Left ventricular mass and interventricular septum were highest in the SHR + M + NaCl group ( P < 0.05), while ejection fraction was lowest in the SHR + M + NaCl group ( P < 0.05). Hematoxylin and eosin staining showed myocardial cell hypertrophy with interstitial fibrosis and localized inflammatory cell infiltration, in the hypertensive groups, particularly in the SHR + M + NaCl group. Electron microscopy showed different degrees of mitochondrial cavitation in heart tissue of the hypertensive groups, which was highest in the SHR + M + NaCl group. In hypertensive animals, levels of reactive oxygen species were highest in the SHR + M + NaCl group ( P < 0.05). Expression of the voltage-dependent anion channel (VDAC) and the apoptosis regulator Bax were highest in the SHR + M + NaCl group ( P < 0.05), which also showed evidence of VDAC and Bax colocalization ( P < 0.05). Overall, these data suggest that mitochondrial tRNA mutation with high-salt stimulation can aggravate cardiac damage, potentially because of increased expression and interaction between Bax and VDAC and increased reactive oxygen species formation and initiation of apoptosis.

Abstract 062: Mitoubiquinone Decreases Reactive Oxygen Species Production and Improves Cardiac Efficiency in Chronic Volume Overload

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Danielle M Yancey ◽  
James D Gladden ◽  
Jason L Guichard ◽  
Victor M Darley-Usmar ◽  
Louis J Dell’Italia ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Membrane Potential ◽  
Systolic Pressure ◽  
Reactive Oxygen ◽  
Volume Overload ◽  
Left Ventricular ◽  
Ros Production ◽  
Oxygen Species ◽  
Cardiac Efficiency ◽  
Lv Dysfunction

Background: The hemodynamic stress of left ventricular (LV) volume overload (VO) produces LV dysfunction accompanied by mitochondrial and cytoskeletal disruption in cardiomyocytes. Because mitochondria are both a source and target of reactive oxygen species (ROS), we hypothesize myocyte damage and LV dysfunction are mediated by mitochondrially produced ROS and can be attenuated by the mitochondrially targeted antioxidant, mitoubiquinone (MitoQ). Methods: Aortocaval fistula (ACF) was induced for 8 weeks in adult rats ± MitoQ. Echocardiography and high-fidelity LV pressure catheter recordings were used to study the LV end-systolic pressure-volume relationship and cardiac efficiency. Isolated cardiomyocytes were loaded with Carboxy-H2DFFDA (CM-DCF) and tetramethylrhodamine (TMRM) to measure mitochondrial ROS production and membrane potential. Results: Isolated cardiomyocyte studies demonstrated increased ROS production and decreased mitochondrial membrane potential in VO animals, both of which were attenuated with MitoQ. Treatment with MitoQ demonstrated a strong trend toward improvement in LV contractility, as cardiac efficiency improved significantly in MitoQ-treated VO animals. Untreated VO animals exhibited mitochondrial swelling and myofibrillar disruption that was prevented by MitoQ. Conclusion: These studies suggest an early interplay between mitochondrial-derived ROS production and cardiac ultrastructure and function.

scholarly journals Loss of Bradykinin Signaling Does Not Accelerate the Development of Cardiac Dysfunction in Type 1 Diabetic Akita Mice

Endocrinology ◽  
2010 ◽  
Vol 151 (8) ◽  
pp. 3536-3542 ◽  
Author(s):  
Adam R. Wende ◽  
Jamie Soto ◽  
Curtis D. Olsen ◽  
Karla M. P. Pires ◽  
John C. Schell ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Reactive Oxygen ◽  
Left Ventricular ◽  
Oxygen Species ◽  
Receptor Signaling ◽  
Genetic Ablation ◽  
Akita Mice

Bradykinin signaling has been proposed to play either protective or deleterious roles in the development of cardiac dysfunction in response to various pathological stimuli. To further define the role of bradykinin signaling in the diabetic heart, we examined cardiac function in mice with genetic ablation of both bradykinin B1 and B2 receptors (B1RB2R−/−) in the context of the Akita model of insulin-deficient type 1 diabetes (Ins2Akita/+). In 5-month-old diabetic and nondiabetic, wild-type and B1RB2R−/− mice, in vivo cardiac contractile function was determined by left-ventricular (LV) catheterization and echocardiography. Reactive oxygen species levels were measured by 2′-7′-dichlorofluorescein diacetate fluorescence. Mitochondrial function and ATP synthesis were determined in saponin-permeabilized cardiac fibers. LV systolic pressure and the peak rate of LV pressure rise and decline were decreased with diabetes but did not deteriorate further with loss of bradykinin signaling. Wall thinning and reduced ejection fractions in Akita mouse hearts were partially attenuated by B1RB2R deficiency, although other parameters of LV function were unaffected. Loss of bradykinin signaling did not increase fibrosis in Ins2Akita/+ diabetic mouse hearts. Mitochondrial dysfunction was not exacerbated by B1RB2R deficiency, nor was there any additional increase in tissue levels of reactive oxygen species. Thus, loss of bradykinin B2 receptor signaling does not abrogate the previously reported beneficial effect of inhibition of B1 receptor signaling. In conclusion, complete loss of bradykinin expression does not worsen cardiac function or increase myocardial fibrosis in diabetes.

scholarly journals Apocynin and Tempol ameliorate dietary sodium-induced declines in cutaneous microvascular function in salt-resistant humans

2019 ◽  
Vol 317 (1) ◽  
pp. H97-H103 ◽  
Author(s):  
Meghan G. Ramick ◽  
Michael S. Brian ◽  
Evan L. Matthews ◽  
Jordan C. Patik ◽  
Douglas R. Seals ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Vascular Function ◽  
Reactive Oxygen ◽  
Microvascular Function ◽  
High Salt ◽  
Dietary Sodium ◽  
Oxygen Species ◽  
High Sodium ◽  
Cutaneous Vasodilation

It has previously been shown that high dietary salt impairs vascular function independent of changes in blood pressure. Rodent studies suggest that NADPH-derived reactive oxygen species mediate the deleterious effect of high salt on the vasculature, and here we translate these findings to humans. Twenty-nine healthy adults (34 ± 2 yr) participated in a controlled feeding study. Participants completed 7 days of a low-sodium diet (LS; 20 mmol sodium/day) and 7 days of a high-sodium diet (HS; 300 mmol sodium/day) in random order. All participants were salt resistant, defined as a ≤5-mmHg change in 24-h mean BP determined while on the LS and HS diets. Laser Doppler flowmetry was used to assess cutaneous vasodilation in response to local heating (42°C) during local delivery of Ringer’s ( n = 29), 20 mM ascorbic acid (AA; n = 29), 10 µM Tempol ( n = 22), and 100 µM apocynin ( n = 22). Additionally, endothelial cells were obtained in a subset of participants from an antecubital vein and stained for nitrotyrosine ( n = 14). Cutaneous vasodilation was attenuated by the HS diet compared with LS [LS 93.0 ± 2.2 vs. HS 86.8 ± 2.0 percentage of maximal cutaneous vascular conductance (%CVCmax); P < 0.05] and was restored by AA during the HS diet (AA 90.7 ± 1.2 %CVCmax; P < 0.05 vs. HS). Cutaneous vasodilation was also restored with the local infusion of both apocynin ( P < 0.01) and Tempol ( P < 0.05) on the HS diet. Nitrotyrosine expression was increased on the HS diet compared with LS ( P < 0.05). These findings provide direct evidence of dietary sodium-induced endothelial cell oxidative stress and suggest that NADPH-derived reactive oxygen species contribute to sodium-induced declines in microvascular function. NEW & NOTEWORTHY High-sodium diets have deleterious effects on vascular function, likely mediating, in part, the increased cardiovascular risk associated with a high sodium intake. Local infusion of apocynin and Tempol improved microvascular function in salt-resistant adults on a high-salt diet, providing evidence that reactive oxygen species contribute to impairments in microvascular function from high salt. This study provides insight into the blood pressure-independent mechanisms by which dietary sodium impairs vascular function. Listen to this article’s corresponding podcast at https://ajpheart.podbean.com/e/dietary-sodium-oxidative-stress-and-microvascular-function/ .

scholarly journals Chronic inhibition of phosphodiesterase 5 with tadalafil attenuates mitochondrial dysfunction in type 2 diabetic hearts: potential role of NO/SIRT1/PGC-1α signaling

2014 ◽  
Vol 306 (11) ◽  
pp. H1558-H1568 ◽  
Author(s):  
Saisudha Koka ◽  
Hema S. Aluri ◽  
Lei Xi ◽  
Edward J. Lesnefsky ◽  
Rakesh C. Kukreja
Keyword(s):  
Reactive Oxygen Species ◽  
Mitochondrial Dysfunction ◽  
Complex I ◽  
Chronic Treatment ◽  
Reactive Oxygen ◽  
Left Ventricular ◽  
Oxygen Species ◽  
Phosphodiesterase 5 ◽  
Type 2 Diabetic

Enhanced nitric oxide (NO) production is known to activate silent information regulator 1 (SIRT1), which is a histone deacetylase that regulates PGC-1α, a regulator of mitochondrial biogenesis and coactivator of transcription factors impacting energy homeostasis. Since phosphodiesterase-5 inhibitors potentiate NO signaling, we hypothesized that chronic treatment with phosphodiesterase-5 inhibitor tadalafil would activate SIRT1-PGC-1α signaling and protect against metabolic stress-induced mitochondrial dysfunction in diabetic hearts. Diabetic db/db mice ( n = 32/group; 40 wk old) were randomized to receive DMSO (10%, 0.2 ml ip) or tadalafil (1 mg/kg ip in 10% DMSO) for 8 wk. Wild-type C57BL mice served as nondiabetic controls. The hearts were excised and homogenized to study SIRT1 activity and downstream protein targets. Mitochondrial function was determined by measuring oxidative phosphorylation (OXPHOS), and reactive oxygen species generation was studied in isolated mitochondria. Tadalafil-treated diabetic mice demonstrated significantly improved left ventricular function, which is associated with increased cardiac SIRT1 activity. Tadalafil also enhanced plasma NO oxidation levels, myocardial SIRT1, PGC-1α expression, and phosphorylation of eNOS, Akt, and AMPK in the diabetic hearts. OXPHOS with the complex I substrate glutamate was decreased by 50% in diabetic hearts compared with the nondiabetic controls. Tadalafil protected OXPHOS with an improved glutamate state 3 respiration rates. The increased reactive oxygen species production from complex I was significantly decreased by tadalafil treatment. In conclusion, chronic treatment with tadalafil activates NO-induced SIRT1-PGC-1α signaling and attenuates mitochondrial dysfunction in type 2 diabetic hearts.

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