[show abstract][hide abstract] ABSTRACT: Excessive iron accumulation leads to iron toxicity in the brain; however the underlying mechanism is unclear. We investigated the effects of iron overload induced by high iron-diet consumption on brain mitochondrial function, brain synaptic plasticity and learning and memory. Iron chelator (deferiprone) and antioxidant (n-acetyl cysteine) effects on iron-overload brains were also studied.
Male Wistar rats were fed either normal diet or high iron-diet consumption for 12 weeks, after which rats in each diet group were treated with vehicle or deferiprone (50 mg/kg) or n-acetyl cysteine (100 mg/kg) or both for another 4 weeks. High iron-diet consumption caused brain iron accumulation, brain mitochondrial dysfunction, impaired brain synaptic plasticity and cognition, blood-brain-barrier breakdown, and brain apoptosis. Although both iron chelator and antioxidant attenuated these deleterious effects, combined therapy provided more robust results.
In conclusion, this is the first study demonstrating that combined iron chelator and anti-oxidant therapy completely restored brain function impaired by iron overload.
PLoS ONE 01/2014; 9(1):e85115. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Aim:We hypothesized that dipeptidyl peptidase (DPP)-4 inhibitor (vildagliptin) reduces fatal arrhythmias, cardiac dysfunction and infarct size caused by ischaemia-reperfusion (I/R) injury via its attenuation of cardiac mitochondrial dysfunction.Methods:In total, 26 rats were randomized to receive either 1 mL normal saline solution or 2.0 mg/kg vildagliptin intravenously (n = 13/group) 30 min prior to a 30-min left anterior descending coronary artery occlusion, followed by a 120-min reperfusion. Arrhythmia scores, cardiac functions, infarct size and mitochondrial function were evaluated.Results:Vildagliptin reduced the infarct size by 44% and mitigated cardiac dysfunction by preserving cardiac function without altering the incidence of cardiac arrhythmias. Vildagliptin increased expression of Bcl-2 and pro-caspase3 in the ischaemic area, whereas Bax and phosphorylated-connexin43/total-connexin43 were not altered. Vildagliptin attenuated cardiac mitochondrial dysfunction by reducing the reactive oxygen species level and mitochondrial swelling.Conclusions:DPP-4 inhibitor provides cardioprotection by reducing the infarct size and ameliorating cardiac dysfunction in I/R hearts by attenuating cardiac mitochondrial dysfunction and cardiomyocyte apoptosis.
Diabetes & Vascular Disease Research 12/2013; · 2.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: Garlic has been shown to exhibit antioxidant effects and cardioprotective properties. However, the effects of garlic extract on the heart in insulin resistance induced by long-term high-fat-diet consumption are not well defined. Therefore, we sought to determine the effects of garlic extract in the obese insulin-resistant rats.
Male Wistar rats (180-200 g) were divided into two groups: normal-diet or high-fat-diet (n = 24/group) fed for 12 weeks. Rats in each groups were divided into three subgroups (n = 8 each): vehicle or garlic extract (250 or 500 mg/kg/day, respectively) treated for 28 days. At the end of the treatment, the metabolic parameters, heart rate variability (HRV), cardiac function, and cardiac mitochondrial function were determined.
Rats that received a high-fat-diet for 12 weeks had increased body weight, visceral fat, plasma insulin levels, total cholesterol, oxidative stress levels, depressed HRV, and cardiac mitochondrial dysfunction. Garlic extract at both concentrations significantly decreased the plasma insulin, total cholesterol, homeostasis model assessment index, and oxidative stress levels. Furthermore, garlic extract at both doses restored the HRV, cardiac function, and cardiac mitochondrial function.
We concluded that garlic extract at both concentrations exerted cardioprotective effects against cardiac dysfunction and mitochondrial dysfunction in obese insulin-resistant rats.
European Journal of Nutrition 10/2013; · 3.13 Impact Factor
[show abstract][hide abstract] ABSTRACT: Iron overload in the heart can lead to iron overload cardiomyopathy and cardiac arrhythmia. In past decades, growing evidence has suggested that cardiac mitochondrial dysfunction is associated with development of cardiac dysfunction and lethal arrhythmias. Despite these facts, the effect of iron overload on cardiac mitochondrial function is still unclear. In this study, we determined the effects of iron overload on the cardiac mitochondrial function and the routes of cardiac mitochondrial iron uptake. We tested the hypothesis that iron overload can lead to cardiac mitochondrial dysfunction, and that mitochondrial calcium uniporter (MCU) plays a major role for cardiac mitochondrial iron uptake under iron overload condition. Cardiac mitochondrial function was assessed via the determination of mitochondrial swelling, mitochondrial reactive oxygen species (ROS) production, and mitochondrial membrane potential changes.
Isolated cardiac mitochondria from male Wistar rats were used in this study. To determine the routes for cardiac mitochondrial iron uptake, isolated mitochondria were exposed to MCU blocker (Ru360), mitochondrial permeability transition pore (mPTP) blocker (Cyclosporin A) and an iron chelator (Deferoxamine).
We found that 1) iron overload caused cardiac mitochondrial dysfunction, indicated by increased ROS production, mitochondrial membrane depolarization and mitochondrial swelling, 2) only MCU blocker completely protected cardiac mitochondrial dysfunction caused by iron overload.
These findings strongly suggest that MCU could be the major route for iron uptake into cardiac mitochondria. The inhibition of MCU could be the novel pharmacological intervention for preventing iron overload cardiomyopathy. This article is protected by copyright. All rights reserved.
[show abstract][hide abstract] ABSTRACT: Myocardial siderosis is known as the major cause of death in thalassemia major (TM) patients since it can lead to iron overload cardiomyopathy. Although this condition can be prevented if timely effective intensive chelation is given to patients, the mortality rate of iron overload cardiomyopathy still remains high due to late detection of this condition. Various direct and indirect methods of iron assessment, including serum ferritin level, echocardiogram, non-transferrin-bound iron, cardiac magnetic resonance T2*, heart rate variability, and liver biopsy and myocardial biopsy, have been proposed for early detection of cardiac iron overload in TM patients. However, controversial evidence and limitations of their use in clinical practice exist. In this review article, all of these iron assessment methods that have been proposed or used to directly or indirectly determine the cardiac iron status in TM reported from both basic and clinical studies are comprehensively summarized and presented. Since there has been growing evidence in the past decades that cardiac magnetic resonance imaging as well as cardiac autonomic status known as the heart rate variability can provide early detection of cardiac involvement in TM patients, these two methods are also presented and discussed. The existing controversy regarding the assessment of cardiac involvement in thalassemia is also discussed.
World journal of cardiology. 08/2013; 5(8):270-279.
[show abstract][hide abstract] ABSTRACT: Right cervical VNS provides cardioprotective effects against acute ischemia-reperfusion injury in small animals. However, inconsistent findings have been reported.
The purpose of this study was to determine whether low-amplitude, left cervical vagus nerve stimulation (VNS) applied either intermittently or continuously imparts cardioprotection against acute ischemia-reperfusion injury.
Thirty-two isoflurane-anesthetized swine (25-30 kg) were randomized into 4 groups: Control (sham operated, no VNS), Continuous-VNS (C-VNS, 3.5mA, 20Hz), Intermittent-VNS (I-VNS, continuously recurring cycles of 21-s ON, 30-s OFF), and I-VNS+Atropine (1mg/kg). Left cervical VNS was applied immediately after left anterior ascending artery (LAD) occlusion (60 min), and continued until the end of reperfusion (120 min). The ischemic and non-ischemic myocardium was harvested for cardiac mitochondrial function assessment.
VNS significantly reduced infarct size, improved ventricular function, decreased VF episodes, and attenuated cardiac mitochondrial reactive oxygen species (ROS) production, depolarization and swelling, compared to Control. However, I-VNS produced the most profound cardioprotective effects, particularly infarct size reduction and decreased ventricular fibrillation episodes, compared to Control and C-VNS. These beneficial effects of VNS were abolished by atropine.
During ischemia-reperfusion injury, both C-VNS and I-VNS provide significant cardioprotective effects compared to Control. These beneficial effects were abolished by muscarinic blockade, suggesting the importance of muscarinic receptor modulation during VNS. The protective effects of VNS could be due to its protection of mitochondrial function during ischemia-reperfusion.
Heart rhythm: the official journal of the Heart Rhythm Society 08/2013; · 4.56 Impact Factor
[show abstract][hide abstract] ABSTRACT: INTRODUCTION: A 3-antibiotic combination (3Mix) is widely used in endodontics for root canal disinfection, particularly in pulp revascularization procedures. However, the cytotoxicity of 3Mix has not been evaluated. The purpose of this study was to determine the cytotoxicity and antibacterial efficacy of 3Mix and each single antibiotic component of 3Mix. METHODS: For the cytotoxicity test, human dental pulp cells and apical papilla cells were exposed to either 3Mix or to each single antibiotic component of 3Mix using concentrations of 0.024, 0.097, 0.39, 1.56, 6.25, and 25.00 μg/mL for 1, 3, 5, and 7 days. Cell viability was determined using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay. For the antibacterial test, 25.00 μg/mL and 0.39 μg/mL 3Mix or single antibiotic were tested on bacteria isolated from necrotic teeth by measuring bacterial recovery on blood agar. RESULTS: The 0.024-μg/mL concentration of all experimental groups generated the highest dental pulp cell or apical pulp cell viability at all time periods. On day 7, 0.39 μg/mL 3Mix produced more than 90% cell viability; 25.00 μg/mL 3Mix completely eliminated isolated bacteria, whereas 0.39 μg/mL was unable to eradicate all bacteria. However, the overall bacterial reduction was significantly different compared with the control group (P < .01). CONCLUSIONS: All drugs except metronidazole induced cytotoxicity on cultured cells. 3Mix generated higher cytotoxicity compared with a single drug. The cytotoxicity increased in a concentration- and time-dependent manner; 0.39 μg/mL 3Mix had less cytotoxicity and was able to significantly reduce bacteria isolated from necrotic teeth.
Journal of endodontics 06/2013; 39(6):813-819. · 2.95 Impact Factor
[show abstract][hide abstract] ABSTRACT: Recent evidence has demonstrated that insulin resistance is related to the development of Type 2 Diabetes Mellitus. Our previous study found that high-fat diet consumption caused not only peripheral and brain insulin resistance, but also brain mitochondrial dysfunction and cognitive impairment. Vildagliptin and sitagliptin, dipeptidyl-peptidase-4 inhibitors, are recently developed anti-diabetic drugs. However, the effects of both drugs on cognitive behaviors and brain mitochondrial function in high-fat diet induced insulin resistant rats have not yet been investigated. Sixty male Wistar rats were divided into 2 groups to receive either normal diet or high-fat diet for 12 weeks. Rats in each group were then further divided into 3 treatment groups to receive either vehicle, vildagliptin (3 mg/kg/day) or sitagliptin (30 mg/kg/day) for 21 days. The cognitive behaviors of the rats were tested using the Morris Water Maze test. Blood samples were collected to determine metabolic parameters and plasma oxidative stress levels. Upon completion of the study, animals were euthanized and the brains removed to investigate brain and hippocampal mitochondrial function as well as oxidative stress levels. We demonstrated that both drugs significantly improved the metabolic parameters and decreased circulating and brain oxidative stress levels in high-fat diet induced insulin resistant rats. In addition, both drugs completely prevented brain and hippocampal mitochondrial dysfunction and equally improved the learning behaviors impaired by high-fat diet. Our findings suggest that the inhibition of dipeptidyl-peptidase-4 enzymes with vildagliptin or sitagliptin in insulin-resistant rats not only increases peripheral insulin sensitivity but also decreases brain dysfunction.
Journal of Endocrinology 04/2013; · 4.06 Impact Factor
[show abstract][hide abstract] ABSTRACT: Previous studies have demonstrated that decreased bone mass results from either the impairment of osteoblastic insulin signaling or obesity. Our previous study revealed that 12-week high-fat-diet (HFD) consumption caused obesity as well as peripheral and brain insulin resistance. However, the osteoblastic insulin resistance induced by HFD has not been elucidated. Therefore, we hypothesized that 12-week HFD rats exhibited not only peripheral insulin resistance but also osteoblastic insulin resistance, which leads to decreased jawbone quality. We found that the jawbones of rats fed a 12-week HFD exhibited increased osteoporosis. The osteoblastic cells isolated from HFD-fed rats exhibited the impairment of osteoblastic insulin signaling as well as reduction of cell proliferation and survival. In conclusion, this study demonstrated that insulin resistance induced by 12-week HFD impaired osteoblastic insulin signaling, osteoblast proliferation, and osteoblast survival and resulted in osteoporosis in the jawbone.
Journal of dental research 04/2013; · 3.46 Impact Factor
[show abstract][hide abstract] ABSTRACT: BACKGROUND AND PURPOSE: Long-term high-fat diet (HFD) consumption has been shown to cause insulin resistance, which is characterized by hyperinsulinemia with metabolic inflexibility. Insulin resistance is associated with cardiac sympathovagal imbalance, cardiac dysfunction, and cardiac mitochondrial dysfunction. Dipeptidyl peptidase-4 (DPP-4) inhibitors, vildagliptin and sitagliptin, are oral anti-diabetic drugs often prescribed in patients with cardiovascular disease. Therefore, in this study, we sought to determine the effects of vildagliptin and sitagliptin in a murine model of insulin resistance. EXPERIMENTAL APPROACH: Male Wistar rats weighing 180-200 g, were fed either a normal diet (20 % energy from fat) or a HFD (59% energy from fat) for 12 weeks. These rats were then divided into 3 subgroups to receive vildagliptin (3 mg/kg/day), sitagliptin (30 mg/kg/day), or vehicle for another 21 days. Metabolic parameters, oxidative stress, heart rate variability (HRV), cardiac function, and cardiac mitochondrial function were determined. KEY RESULTS: Rats that received HFD developed insulin resistance characterized by increased body weight, plasma insulin, total cholesterol, and oxidative stress levels along with a decreased high-density lipoprotein (HDL) level. Moreover, cardiac dysfunction, depressed HRV, cardiac mitochondrial dysfunction, and cardiac mitochondrial morphology changes were observed in HFD rats. Both vildagliptin and sitagliptin decreased plasma insulin, total cholesterol, and oxidative stress as well as increased HDL level. Furthermore, vildagliptin and sitagliptin attenuated cardiac dysfunction, prevented cardiac mitochondrial dysfunction, and completely restored HRV. CONCLUSIONS AND IMPLICATIONS: Both vildagliptin and sitagliptin share similar efficacy in cardioprotection in obese insulin resistant rats.
British Journal of Pharmacology 03/2013; · 5.07 Impact Factor
[show abstract][hide abstract] ABSTRACT: Insulin resistance is associated with the impairment of the response of insulin receptor to insulin, resulting in the reduction of glucose uptake, leading to the alteration of myocardial glucose metabolism, impairment of cardiac electrophysiology, and increased susceptibility to ischemia-induced myocardial injury. Insulin resistance is associated with the impairment of the intracellular insulin signal transduction pathway. Among the MAPK family, p38-MAPK is a serine/threonine protein kinase, which has been shown to play an important role in cellular responses to various kinds of stress, including insulin resistance. Since growing evidence indicates the involvement of p38-MAPK in cardiovascular dysfunction, it is possible that the activation of p38-MAPK is responsible in part as a causative mechanism for cardiovascular complications in the insulin resistant heart. In addition, several anti-diabetic drugs have been shown to affect the myocardial p38-MAPK pathway. The effect of these drugs on p38-MAPK could be associated with their cardiovascular results in patients with insulin resistance. In this article, the signal transduction pathways of myocardial p38-MAPK activation in the insulin resistant heart, as well as the effects of anti-diabetic drugs on the myocardial p38-MAPK pathway, are comprehensively reviewed. Furthermore, the possible therapeutic approach regarding the utilization of a p38-MAPK inhibitor in diabetes patients to prevent cardiovascular complications is also addressed.
Current pharmaceutical design 02/2013; · 4.41 Impact Factor
[show abstract][hide abstract] ABSTRACT: AIMS: Although iron overload induces oxidative stress and brain mitochondrial dysfunction, and is associated with neurodegenerative diseases, brain mitochondrial iron uptake has not been investigated. We determined the role of mitochondrial calcium uniporter (MCU) in brain mitochondria as a major route for iron entry. We hypothesized that iron overload causes brain mitochondrial dysfunction, and that the MCU blocker prevents iron entry into mitochondria, thus attenuating mitochondrial dysfunction. MAIN METHODS: Isolated brain mitochondria from male Wistar rats were used. Iron (Fe(2+) and Fe(3+)) at 0-286μM were applied onto mitochondria at various incubation times (5-30minutes), and the mitochondrial function was determined. Effects of MCU blocker (Ru-360) and iron chelator were studied. KEY FINDINGS: Both Fe(2+) and Fe(3+) entered brain mitochondria and caused mitochondrial swelling in a dose- and time-dependent manner, and caused mitochondrial depolarization and increased ROS production. However, Fe(2+) caused more severe mitochondrial dysfunction than Fe(3+). Although all drugs attenuated mitochondrial dysfunction caused by iron overload, only an MCU blocker could completely prevent ROS production and mitochondrial depolarization. SIGNIFICANCE: Our findings indicated that iron overload caused brain mitochondrial dysfunction, and that an MCU blocker effectively prevented this impairment, suggesting that MCU could be the major portal for brain mitochondrial iron uptake.
[show abstract][hide abstract] ABSTRACT: Despite debates regarding its cardioprotection and pro-arrhythmia, the definite mechanisms of rosiglitazone on the heart are still unclear. We determined the mechanistic effects of rosiglitazone on cardiac function, arrhythmias and infarct size during cardiac ischemic/reperfusion (I/R). Methods: Twenty-six rats were utilized. In each rat, either rosiglitazone or saline solution was administered intravenously prior to a 30-minute left anterior descending coronary artery ligation and a 120-minute reperfusion. Cardiac function, infarct size, myocardial level of connexin43, Bax/Bcl-2, cytochrome-c, caspase-3, caspase-8, Akt, TNF-α, IL-4, and cardiac mitochondrial function were determined. Isolated cardiomyocytes were used for studying intracellular calcium. Results: Rosiglitazone did not alter cardiac function during the I/R periods, but increased the arrhythmia score and mortality rate, decreased the time to ventricular fibrillation onset, and prolonged Ca2+ decay rate, compared to the saline group (P<0.05). However, the infarct size in the rosiglitazone group was decreased (P<0.05). Rosiglitazone decreased the levels of connexin43 phosphorylation, active caspase-8, and TNF-α, but increased the procaspase-3 level. However, levels of Bax/Bcl-2, cytochrome-c, Akt, IL-4, and cardiac mitochondrial function were not different between the two groups. Conclusions: Rosiglitazone simultaneously exerted both beneficial and adverse cardiac effects in the I/R heart. Although it decreased the infarct size via the extrinsic anti-apoptotic pathway, and anti-inflammation, rosiglitazone facilitated a fatal arrhythmia by decreasing the connexin43 phosphorylation, and prolonging the Ca2+ decay rate in I/R rats. The higher mortality rate in the rosiglitazone group suggests that its undesirable effect was more pronounced than its benefit on infarct size reduction.
[show abstract][hide abstract] ABSTRACT: Background & objectives: Pre-clinical studies in swine have demonstrated that a supratherapeutic concentration of sildenafil citrate decreased defibrillation efficacy and facilitated cardiac arrhythmia. We therefore, decided to investigate the effects of Kaempferia parviflora (KP) extract on these parameters in the swine heart. The underlying assumption was that in the heart, KP might be producing effects similar to sildanafil citrate as KP has long been used in southeast Asian traditional medicine to correct erectile dysfunction. Methods: The study was conducted as the defibrillation study, and ventricular fibrillation (VF) induction study. In both studies, the defibrillation threshold (DFT), the upper limit of vulnerability (ULV) and VF threshold were determined before and after KP extract administration. Results: In both studies KP extract at high concentrations (100 and 50 mg/kg) significantly increased the DFT and ULV, without altering the VF threshold. At these concentrations, systolic and diastolic blood pressures were also attenuated. Interpretation & conclusions: High concentrations of KP extract attenuated defibrillation efficacy and increased cardiac vulnerability to arrhythmia in a normal swine heart. When used in appropriate concentrations, its blood pressure lowering effect may be useful in hypertensive states. Further studies need to be done to elucidate its mechanism of action.
The Indian Journal of Medical Research 01/2013; 137(1):156-163. · 2.06 Impact Factor
[show abstract][hide abstract] ABSTRACT: High-fat diet (HFD) consumption has been demonstrated to cause peripheral and neuronal insulin resistance, and brain mitochondrial dysfunction in rats. Although the dipeptidyl peptidase-4 inhibitor, vildagliptin, is known to improve peripheral insulin sensitivity, its effects on neuronal insulin resistance and brain mitochondrial dysfunction caused by a HFD are unknown. We tested the hypothesis that vildagliptin prevents neuronal insulin resistance, brain mitochondrial dysfunction, learning and memory deficit caused by HFD. Male rats were divided into two groups to receive either a HFD or normal diet (ND) for 12 weeks, after which rats in each group were fed with either vildagliptin (3 mg/kg/day) or vehicle for 21 days. The cognitive function was tested by the Morris Water Maze prior to brain removal for studying neuronal insulin receptor (IR) and brain mitochondrial function. In HFD rats, neuronal insulin resistance and brain mitochondrial dysfunction were demonstrated, with impaired learning and memory. Vildagliptin prevented neuronal insulin resistance by restoring insulin-induced long-term depression and neuronal IR phosphorylation, IRS-1 phosphorylation and Akt/PKB-ser phosphorylation. It also improved brain mitochondrial dysfunction and cognitive function. Vildagliptin effectively restored neuronal IR function, increased glucagon-like-peptide 1 levels and prevented brain mitochondrial dysfunction, thus attenuating the impaired cognitive function caused by HFD.
European Journal of Neuroscience 12/2012; · 3.75 Impact Factor
[show abstract][hide abstract] ABSTRACT: The mitogen-activated protein kinases play an important role in ischemia/reperfusion (I/R) injury. Previous evidence suggests that p38 MAPK inhibition prior to ischemia is cardioprotective. However, whether p38 MAPK inhibition during ischemia or reperfusion provides cardioprotection is not well known. We tested the hypothesis that p38 MAPK inhibition at different times during I/R protects the heart from arrhythmias, reduces the infarct size, and attenuates ventricular dysfunction. Adult Wistar rats were subject to a 30-min left anterior descending coronary artery (LAD) occlusion, followed by a 120-min reperfusion. A p38 MAPK inhibitor, SB203580, was given intravenously before LAD occlusion, during ischemia, or at the onset of reperfusion. The results showed that SB203580 given either before or during ischemia, but not at the onset of reperfusion, decreased the ventricular tachycardia/fibrillation (VT/VF) incidence and Heat Shock Protein (HSP) 27 phosphorylation, and increased connexin43 (Cx43) phosphorylation. The infarct size and cytochrome c level was decreased in all SB203580-treated rats, without the alteration of the total Bax/Bcl-2 expression. The ventricular function was improved only in SB203580-pretreated rats. These findings suggest that timing of p38 MAPK inhibition with respect to onset of ischemia is an important determinant of therapeutic efficacy.
Journal of cardiovascular pharmacology 10/2012; · 2.83 Impact Factor
[show abstract][hide abstract] ABSTRACT: Iron-overload cardiomyopathy is a major cause of death in thalassemic patients. However, pathways of non-transferrin-bound iron (NTBI) uptake into cardiomyocytes under iron-overload conditions are still controversial. We previously demonstrated that Fe(2+) uptake in thalassemic cardiomyocytes is mainly mediated by T-type calcium channels (TTCCs). However, direct evidence regarding Fe(3+) uptake, the other form of NTBI, in thalassemic cardiomyocytes has never been investigated. Hearts from genetic-altered β-thalassemic mice and adult wild-type (WT) mice were used for cultured ventricular cardiomyocytes. Blockers for L-type calcium channel (LTCC), TTCC, transferrin receptor1 (TfR1), and divalent metal transporter1 (DMT1) were used, and quantification of cellular iron uptake was performed by the acetoxymethyl ester of calcein fluorescence assay. Cellular uptake of Fe(3+) under iron-overload conditions in cultured ventricular myocytes of thalassemic mice was greater than that of WT cells (P < 0.01). The iron chelator, deferoxamine, could prevent Fe(3+) uptake into cultured cardiomyocytes. However, blockers of TfR1, DMT1, LTCC, and TTCC could not prevent Fe(3+) uptake into cardiomyocytes. Our findings indicated that, unlike Fe(2+), Fe(3+) uptake in cultured thalassemic cardiomyocytes is not mainly mediated by TfR1, DMT1, LTCC, and TTCC, suggesting that another alternative pathway could play a major role in Fe(3+) uptake in thalassemic cardiomyocytes.
Drug and Chemical Toxicology 10/2012; · 1.29 Impact Factor
[show abstract][hide abstract] ABSTRACT: Iron-overload induced cardiomyopathy is a major cause of morbidity and mortality in thalassemic patients. Previous studies suggest that cardiac mitochondrial dysfunction may be involved in the pathogenesis of cardiomyopathy in thalassemia. We tested the hypothesis that iron overload causes dysfunction of cardiac mitochondria isolated from thalassemic mice. Cardiac mitochondria were isolated from the heart tissue of genetically-altered, β-thalassemic mice (HT) and adult wild-type mice (WT). Ferrous iron (Fe(2+)) at various concentrations (0-5 μg/ml) was applied to induce iron toxicity. Pharmacological interventions, facilitated by mitochondrial permeability transition pore (mPTP) blocker, CsA, and mitochondrial Ca(2+) uniporter (MCU) blocker, Ru360, were used to study their respective effects on cardiac mitochondrial dysfunction. Cardiac mitochondrial ROS production, mitochondrial membrane potential changes, and mitochondrial swelling were determined. Iron overload caused increased ROS production, mitochondrial depolarization, and mitochondrial swelling in a dose-dependent manner in WT and HT cardiac mitochondria. CsA decreased only ROS production in WT and HT cardiac mitochondria, whereas Ru360 completely prevented the development of cardiac mitochondrial dysfunction by decreasing ROS, mitochondrial depolarization, and swelling in both WT and HT cardiac mitochondria. Ru360, an MCU blocker, provides protective effects by preventing ROS production and mitochondrial depolarization as well as attenuating mitochondrial swelling caused by Fe(2+) overload. These findings indicate that the MCU could be a major portal for Fe(2+) entry into cardiac mitochondria. Therefore, blocking MCU may be an effective therapy to prevent iron-overload induced cardiac mitochondrial dysfunction in patients with thalassemia.