-
[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; · 3.55 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; · 4.41 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.
Life sciences 01/2013; · 2.56 Impact Factor
-
[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.
Experimental physiology 01/2013; · 3.17 Impact Factor
-
[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. · 1.84 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; · 3.63 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; · 1.08 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: This study examined whether caffeic acid phenethyl ester (CAPE) can protect kidney mitochondria against cadmium toxicity. Kidney mitochondria isolated from Wistar rat were exposed to cadmium and/or CAPE at various concentrations. Mitochondrial function, ultrastructure and oxidative stress status were determined. Cadmium exposure resulted in mitochondrial swelling, dissipation of membrane potential, overproduction of reactive oxygen species, and impaired ultrastructure. The injury was accompanied by an increase in mitochondrial nitric oxide and malondialdehyde levels as well as a decrease in superoxide dismutase activity and antioxidant thiols. Pretreatment with CAPE ameliorated all the changes caused by cadmium. The results suggest a promising role for CAPE as mitochondria-targeted antioxidant to combat the renal toxicity of cadmium.
Chemico-biological interactions 09/2012; 200(1):21-7. · 2.46 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.
Biology of Metals 08/2012; · 3.17 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Metformin is a first line drug for the treatment of type 2 diabetes mellitus (T2DM). Our previous study reported that high-fat diet (HFD) consumption caused not only peripheral and neuronal insulin resistance, but also induced brain mitochondrial dysfunction as well as learning impairment. However, the effects of metformin on learning behavior and brain mitochondrial functions in HFD-induced insulin resistant rats have never been investigated.
Thirty-two male Wistar rats were divided into two groups to receive either a normal diet (ND) or a high-fat diet (HFD) for 12weeks. Then, rats in each group were divided into two treatment groups to receive either vehicle or metformin (15mg/kg BW twice daily) for 21days. All rats were tested for cognitive behaviors using the Morris water maze (MWM) test, and blood samples were collected for the determination of glucose, insulin, and malondialdehyde. At the end of the study, animals were euthanized and the brain was removed for studying brain mitochondrial function and brain oxidative stress.
We found that in the HFD group, metformin significantly attenuated the insulin resistant condition by improving metabolic parameters, decreasing peripheral and brain oxidative stress levels, and improving learning behavior, compared to the vehicle-treated group. Furthermore, metformin completely prevented brain mitochondrial dysfunction caused by long-term HFD consumption.
Our findings suggest that metformin effectively improves peripheral insulin sensitivity, prevents brain mitochondrial dysfunction, and completely restores learning behavior, which were all impaired by long-term HFD consumption.
Life sciences 08/2012; 91(11-12):409-14. · 2.56 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Cardiac mitochondrial Ca(2+) overload plays a critical role in mechanical and electrical dysfunction leading to cardiac cell death and fatal arrhythmia. Because Ca(2+) overload is related to mitochondrial permeability transition, reactive oxygen species (ROS) production and membrane potential (ΔΨm) dissipation, we probed the mechanistic association between Ca(2+) overload, oxidative stress, mitochondrial permeability transition pore (mPTP) and mitochondrial calcium uniporter (MCU) in isolated cardiac mitochondria.
Various concentrations of Ca(2+) (5-200 μM) were used to induce mitochondrial dysfunction. Cyclosporin A (CsA, an mPTP blocker) and Ru360 (an MCU blocker) were used to test its protective effects on Ca(2+)-induced mitochondrial dysfunction.
High concentrations of Ca(2+) (≥100 μM) caused overt mitochondrial swelling and ΔΨm collapse. However, only slight increases in ROS production were detected. Blocking the MCU by Ru360 is less effective in protecting mitochondrial dysfunction.
A dominant cause of Ca(2+)-induced cardiac mitochondrial dysfunction was mediated through the mPTP rather than MCU. Therefore, CsA could be more effective than Ru360 in preventing Ca(2+)-induced cardiac mitochondrial dysfunction.
Archives of medical research 07/2012; 43(5):333-8. · 1.88 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Although Kaempferia parviflora extract (KPE) and its flavonoids have positive effects on the nitric oxide (NO) signaling pathway, its mechanisms on the heart are still unclear. Because our previous studies demonstrated that KPE decreased defibrillation efficacy in swine similar to that of sildenafil citrate, the phosphodiesterase-5 inhibitor, it is possible that KPE may affect the cardiac NO signaling pathway. In the present study, the effects of KPE and sildenafil citrate on cyclic guanosine monophosphate (cGMP) level, modulation of cardiac function, and Ca transients in ventricular myocytes were investigated. In a rat model, cardiac cGMP level, cardiac function, and Ca transients were measured before and after treatment with KPE and sildenafil citrate. KPE significantly increased the cGMP level and decreased cardiac function and Ca transient. These effects were similar to those found in the sildenafil citrate-treated group. Furthermore, the nonspecific NOS inhibitor could abolish the effects of KPE and sildenafil citrate on Ca transient. KPE has positive effect on NO signaling in the heart, resulting in an increased cGMP level, similar to that of sildenafil citrate. This effect was found to influence the physiology of normal heart via the attenuation of cardiac function and the reduction of Ca transient in ventricular myocytes.
Journal of cardiovascular pharmacology 06/2012; 60(3):299-309. · 2.83 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Insulin resistance has been shown to be associated with cardiac sympathovagal imbalance, myocardial dysfunction, and cardiac mitochondrial dysfunction. Whereas metformin is a widely used antidiabetic drug to improve insulin resistance, vildagliptin is a novel oral antidiabetic drug in a group of dipeptidyl peptidase-4 inhibitors in which its cardiac effect is unclear. This study aimed to determine the cardiovascular effects of metformin and vildagliptin in rats with insulin resistance induced by high-fat diet. Male Wistar rats were fed with either a normal diet or high-fat diet (n =24 each) for 12 wk. Rats in each group were divided into three subgroups to receive the vehicle, metformin (30 mg/kg, twice daily), or vildagliptin (3 mg/kg, once daily) for another 21 d. Heart rate variability (HRV), cardiac function, and cardiac mitochondrial function were determined and compared among these treatment groups. Rats exposed to a high-fat diet developed increased body weight, visceral fat, plasma insulin, cholesterol, oxidative stress, depressed HRV, and cardiac mitochondrial dysfunction. Metformin and vildagliptin did not alter body weight and plasma glucose levels but decreased the plasma insulin, total cholesterol, and oxidative stress levels. Although both metformin and vildagliptin attenuated the depressed HRV, cardiac dysfunction, and cardiac mitochondrial dysfunction, vildagliptin was more effective in this prevention. Furthermore, only vildagliptin prevented cardiac mitochondrial membrane depolarization caused by consumption of a high-fat diet. We concluded that vildagliptin is more effective in preventing cardiac sympathovagal imbalance and cardiac dysfunction, as well as cardiac mitochondrial dysfunction, than metformin in rats with insulin resistance induced by high-fat diet.
Endocrinology 05/2012; 153(8):3878-85. · 4.46 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Since variety in response to Ca(2+)-induced mitochondrial dysfunction in different neuronal mitochondrial populations is associated with the pathogenesis of several neurological diseases, we investigated the effects of Ca(2+) overload on synaptic (SM) and nonsynaptic mitochondrial (NM) dysfunction and probed the effects of cyclosporin A (CsA), 4'-chlorodiazepam (CDP) and Ru360 on relieving mitochondrial damage.
SM and NM mitochondria were isolated from rats' brains (n=5/group) and treated with various concentrations (5, 10, 100, and 200 μM) of Ca(2+), with and without CsA (mPTP blocker), CDP (PBR/TSPO blocker) and Ru360 (MCU blocker) pretreatments. Mitochondrial function was determined by mitochondrial swelling, ROS production and mitochondrial membrane potential changes (ΔΨm).
At 200-μM Ca(2+), SM presented mitochondrial swelling to a greater extent than NM. At 100 and 200-μM Ca(2+), the ROS production of SM was higher than that of NM and ΔΨm dissipation of SM was also larger. CsA, CDP and Ru360 could reduce ROS production of SM and NM with exposure to 200-μM Ca(2+). However, only Ru360 could completely inhibit ROS generation in both SM and NM, whereas CsA and CDP could only partially reduce the ROS level in SM. Moreover, CsA and CDP pretreatments were not able to restore ΔΨm. However, Ru360 pretreatment could protect ΔΨm dissipation in both SM and NM, with complete protection observed only in NM.
Our findings suggested that mitochondrial calcium uniporter is a possible major pathway for calcium uptake in both mitochondrial populations. However, SM might have additional pathways involved in the calcium uptake.
Life sciences 04/2012; 90(19-20):808-14. · 2.56 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Incretin is a gut derived peptide hormone secreted in the intestine after food ingestion, and is degraded rapidly after secretion by dipeptidyl peptidase (DPP)-4. Incretin-based therapy, such as glucagon-like peptide (GLP)-1 and the DPP-4 inhibitor, has been proposed as a new therapeutic approach for the treatment of type 2 diabetic patients. In the past few years, growing evidence also demonstrated the cardioprotective effects of incretin-based therapy, especially during ischaemia-reperfusion (I/R) injury in both the animal models and in clinical studies. However, inconsistent reports exist regarding the use of these pharmacological interventions. In this article, a comprehensive review regarding both basic and clinical studies reporting the effects of GLP-1 and DPP-4 inhibitors on I/R hearts is presented and discussed. The consistent findings as well as controversial results are summarised, focusing on the effects of incretin on the infarct size, left ventricular function and haemodynamic improvement during an I/R injury.
Diabetes & Vascular Disease Research 04/2012; 9(4):256-69. · 2.12 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: It is well established that myocardial infarction (MI) associated with coronary artery bypass grafting (CABG) predicts a poor outcome. Nevertheless, cardioprotective therapies to limit myocardial injury after CABG are lacking. Previous studies have shown that curcuminoids decrease proinflammatory cytokines during cardiopulmonary bypass surgery and decrease the occurrence of cardiomyocytic apoptosis after cardiac ischemia/reperfusion injury in animal models. We aimed to evaluate whether curcuminoids prevent MI after CABG compared to placebo. The 121 consecutive patients undergoing CABG were randomly allocated to receive placebo or curcuminoids 4 g/day beginning 3 days before the scheduled surgery and continued until 5 days after surgery. The primary end point was incidence of in-hospital MI. The secondary end point was the effect of curcuminoids on C-reactive protein, plasma malondialdehyde, and N-terminal pro-B-type natriuretic peptide levels. Baseline characteristics were comparable between the curcuminoid and placebo groups. Mean age was 61 ± 9 years. On-pump CABG procedures were performed in 51.2% of patients. Incidence of in-hospital MI was decreased from 30.0% in the placebo group to 13.1% in the curcuminoid group (adjusted hazard ratio 0.35, 0.13 to 0.95, p = 0.038). Postoperative C-reactive protein, malondialdehyde, and N-terminal pro-B-type natriuretic peptide levels were also lower in the curcuminoid than in the placebo group. In conclusion, we demonstrated that curcuminoids significantly decreased MI associated with CABG. The antioxidant and anti-inflammatory effects of curcuminoids may account for their cardioprotective effects shown in this study.
The American journal of cardiology 04/2012; 110(1):40-4. · 3.58 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Iron-overload cardiomyopathy is a major cause of morbidity and mortality in patients with thalassemia. However, the precise mechanisms of iron entry and sequestration in the heart are still unclear. Our previous study showed that Fe(2+) uptake in thalassemic cardiomyocytes are mainly mediated by T-type calcium channels (TTCC). Nevertheless, the role of TTCC as well as other transporters such as divalent metal transporter1 (DMT1) and L-type calcium channels (LTCC) as possible portals for iron entry into the heart in in vivo thalassemic mice under an iron-overload condition has not been investigated.
An iron-overload condition was induced in genetically altered β-thalassemic mice and adult wild-type mice by feeding them with an iron diet (0.2% ferrocene w/w) for 3 months. Then, blockers for LTCC (verapamil and nifedipine), TTCC (efonidipine), and DMT1 (ebselen) as well as iron chelator desferoxamine (DFO) were given for 1 month with continuous iron feeding.
Treatment with LTCC, TTCC, DMT1 blockers, and DFO reduced cardiac iron deposit, cardiac malondialdehyde (MDA), plasma non-transferrin-bound iron, and improved heart rate variability and left ventricular (LV) function in thalassemic mice with iron overload. Only TTCC and DMT1 blockers and DFO reduced liver iron accumulation, liver MDA, plasma MDA, and decreased mortality rate in iron-overloaded thalassemic mice.
DMT1, LTCC, and TTCC played important roles for iron entry in the thalassemic heart under an iron-overloaded condition. Unlike LTCC blocker, TTCC blocker provided all benefits including attenuating iron deposit in both the heart and liver, reduced oxidative stress, and decreased mortality in iron-overloaded mice.
European Journal Of Haematology 03/2012; 88(6):535-48. · 2.61 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitor is a new anti-diabetic drug for type-2 diabetes mellitus patients. Despite its benefits on glycemic control, the effects of DPP-4 inhibitor on the heart during ischemia-reperfusion (I/R) periods are not known. We investigated the effect of DPP-4 inhibitor on cardiac electrophysiology and infarct size in a clinically relevant I/R model in swine and its underlying cardioprotective mechanism. METHODS: Fourteen pigs were randomized to receive either DPP-4 inhibitor (vildagliptin) 50mg or normal saline intravenously prior to a 90-min left anterior descending artery occlusion, followed by a 120-min reperfusion period. The hemodynamic, cardiac electrophysiological and arrhythmic parameters, and the infarct size were determined before and during I/R. Rat cardiac mitochondria were used to study the protective effects of DPP-4 inhibitor on cardiac mitochondrial dysfunction caused by severe oxidative stress induced by H(2)O(2) to mimic the I/R condition. RESULTS: Compared to the saline group, DPP-4 inhibitor attenuated the shortening of the effective refractory period (ERP), decreased the number of PVCs, increased the ventricular fibrillation threshold (VFT) during the ischemic period, and also decreased the infarct size. In cardiac mitochondria, DPP-4 inhibitor decreased the reactive oxygen species (ROS) production and prevented cardiac mitochondrial depolarization caused by severe oxidative stress. CONCLUSIONS: During I/R, DPP-4 inhibitor stabilized the cardiac electrophysiology by preventing the ERP shortening, decreasing the number of PVCs, increasing the VFT, and decreasing the infarct size. This cardioprotective effect could be due to its prevention of cardiac mitochondrial dysfunction caused by severe oxidative stress during I/R.
International journal of cardiology 01/2012; · 7.08 Impact Factor
