[Show abstract][Hide abstract] ABSTRACT: Obese-insulin resistance and type 2 diabetes mellitus (T2DM) have become global health problems, and they are both associated with a higher risk of ischemic heart disease. Although reperfusion therapy is the treatment to increase blood supply to the ischemic myocardium, this intervention potentially causes cardiac tissue damage and instigates arrhythmias, processes known as reperfusion injury. Dipeptidyl peptidase 4 (DPP-4) inhibitors are glycemic control drugs commonly used in T2DM patients. Growing evidence from basic and clinical studies demonstrates that a DPP-4 inhibitor could exert cardioprotection and improve left ventricular function by reducing oxidative stress, apoptosis, and increasing reperfusion injury salvage kinase (RISK) activity. However, recent reports also showed potentially adverse cardiac events due to the use of a DPP-4 inhibitor. To investigate this disparity, future large clinical trials are essential in verifying whether DPP-4 inhibitors are beneficial beyond their glycemic control particularly for the ischemic heart in obese-insulin resistant subjects and T2DM patients.
International journal of cardiology 10/2015; 202:415-416. DOI:10.1016/j.ijcard.2015.09.044 · 4.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Testosterone replacement improves metabolic parameters and cognitive function in hypogonadism. However, the effects of testosterone therapy on cognition in obese condition with testosterone deprivation have not been investigated. We hypothesized that testosterone replacement improves cognitive function in testosterone-deprived obese rats by restoring brain insulin sensitivity, brain mitochondrial function, and hippocampal synaptic plasticity. Thirty male Wistar rats had either a bilateral orchiectomy (ORX: O, n = 24) or a sham operation (S, n = 6). ORX rats were further divided into two groups fed with either a normal diet (NDO) or a high-fat diet (HFO) for 12 weeks. Then, ORX rats in each dietary group were divided into two subgroups (n = 6/subgroup) and were given either castor oil or testosterone (2 mg/kg/day, s.c.) for 4 weeks. At the end of this protocol, cognitive function, metabolic parameters, brain insulin sensitivity, hippocampal synaptic plasticity, and brain mitochondrial function were determined. We found that testosterone replacement increased peripheral insulin sensitivity, decreased circulation and brain oxidative stress levels, and attenuated brain mitochondrial ROS production in HFO rats. However, testosterone failed to restore hippocampal synaptic plasticity and cognitive function in HFO rats. In contrast, in NDO rats, testosterone decreased circulation and brain oxidative stress levels, attenuated brain mitochondrial ROS production, and restored hippocampal synaptic plasticity as well as cognitive function. These findings suggest that testosterone replacement improved peripheral insulin sensitivity and decreased oxidative stress levels, but failed to restore hippocampal synaptic plasticity and cognitive function in testosterone-deprived obese rats. However, it provided beneficial effects in reversing cognitive impairment in testosterone-deprived non-obese rats.
Age 10/2015; 37(5):9827. DOI:10.1007/s11357-015-9827-4 · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Fibroblast growth factor 21 (FGF21) is a novel polypeptide ligand which has been shown to be involved in several physiological and pathological processes including regulation of glucose and lipids, reduction of arteriosclerotic plaque formation in the great vessels and has also been shown to exert cardioprotective effects in myocardial infarction, cardiac ischemia-reperfusion injury, cardiac hypertrophy and diabetic cardiomyopathy. Moreover, FGF21 protects the myocardium and great arteries by attenuating remodeling, inflammation, oxidative stress and also promoting the energy supply to the heart through fatty acid β-oxidation. This growing evidence emphasizes the important roles of FGF21 in cardioprotection. This review comprehensively summarizes and discusses the consistent and inconsistent findings regarding the beneficial effects of FGF21 on the heart available from both basic research and clinical reports. The details of the signaling, biological and pharmacological effects of FGF21 with regard to its protection of the heart are also presented and discussed in this review.
Journal of Endocrinology 09/2015; 227(2). DOI:10.1530/JOE-15-0289 · 3.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Iron-overload cardiomyopathy is a major cause of death in thalassemia patients due to the lack of an early detection strategy. Although cardiac magnetic resonance (CMR) T2* is used for early detection of cardiac iron accumulation, its availability is limited. Heart rate variability (HRV) has been used to evaluate cardiac autonomic function and found to be depressed in thalassemia. However, its direct correlation with cardiac iron accumulation has never been investigated. We investigated whether HRV can be used as an alternative indicator for early identification of cardiac iron deposition in thalassemia patients.
Ninety-nine non-transfusion dependent thalassemia patients (23.00 (17.00, 32.75) years, 35 male) were enrolled. The correlation between HRV recorded using 24-hour Holter monitoring and non-transferrin bound iron (NTBI), hemoglobin (Hb), serum ferritin, LV ejection fraction (LVEF), and CMR-T2* were determined.
The median NTBI value was 3.15 (1.11, 6.59) μM. Both time and frequency domains of HRV showed a significant correlation with the NTBI level, supporting HRV as a marker of iron overload. Moreover, the LF/HF ratio showed a significant correlation with CMR-T2* with the receiver operating characteristic (ROC) curve of 0.684±0.063, suggesting that it could represent the cardiac iron deposit in thalassemia patients. HRV was also significantly correlated with serum ferritin and Hb.
This novel finding regarding the correlation between HRV and CMR-T2* indicates that HRV could be a potential marker in identifying early cardiac iron deposition prior to the development of LV dysfunction, and may be used as an alternative to CMR-T2* for screening cardiac iron status in thalassemia patients.
PLoS ONE 06/2015; 10(6):e0130837. DOI:10.1371/journal.pone.0130837 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Brain mitochondrial dysfunction has been demonstrated in diabetic animals with neurodegeneration. Protocatechuic acid (PCA), a major metabolite of anthocyanin, has been shown to exert glycemic control and oxidative stress reduction in the heart. However, its effects on oxidative stress and mitochondrial function in the brain under diabetic condition have never been investigated. We found that PCA exerted glycemic control, attenuates brain mitochondrial dysfunction, and contributes to the prevention of brain oxidative stress in diabetic rats.
[Show abstract][Hide abstract] ABSTRACT: It is unclear whether the DDP-IV inhibitor can counteract brain insulin resistance, brain mitochondrial dysfunction, impairment of hippocampal synaptic plasticity, and cognitive decline in testosterone-deprived obese rats. We hypothesized that DPP-4 inhibitor vildagliptin improves cognitive function in testosterone-deprived obese rats by restoring brain insulin sensitivity, brain mitochondrial function and hippocampal synaptic plasticity. Thirty male Wistar rats received either a sham-operated (S, n=6) or bilateral orchiectomy (ORX:O, n=24). ORX rats were divided into 2 groups and fed with either a normal diet (NDO) or a high-fat diet (HFO) for 12 weeks. Then, ORX rats in each dietary group were divided into 2 subgroups (n=6/subgroup) to receive either a vehicle or vildagliptin (3 mg/kg/day, p.o.) for 4 weeks. After treatment, cognitive function, metabolic parameters, brain insulin sensitivity, hippocampal synaptic plasticity and brain mitochondrial function were determined in each rat. We found that HFO rats exhibited peripheral and brain insulin resistance, brain mitochondrial dysfunction, impaired hippocampal synaptic plasticity and cognitive decline. NDO rats did not develop peripheral and brain insulin resistance; however, impaired hippocampal synaptic plasticity and cognitive decline occurred. Vildagliptin significantly improved peripheral insulin sensitivity, restored brain insulin sensitivity and decreased brain mitochondrial ROS production in HFO rats. However, vildagliptin did not restore hippocampal synaptic plasticity and cognitive function in both NDO and HFO rats. These findings suggest that vildagliptin could not counteract the impairment of hippocampal synaptic plasticity and cognitive decline in testosterone-deprived subjects, despite of its effects on improved peripheral and brain insulin sensitivity as well as brain mitochondrial function.
Journal of Endocrinology 05/2015; 226(2). DOI:10.1530/JOE-15-0099 · 3.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cardiac cell death and fatal arrhythmias during myocardial ischemia/reperfusion (I/R) can be reduced by p38 MAPK inhibition. However, the effects of p38 MAPK inhibition on cardiac mitochondria have not been investigated.
We tested the hypothesis that p38 MAPK inhibition at different times during I/R protects cardiac mitochondrial functions.
Adult Wistar rats were subjected to 30 min of left anterior descending coronary artery (LAD) occlusion, followed by 120 min of reperfusion. A 2 mg/kg bolus infusion of p38 MAPK inhibitor, SB203580, was given before or during ischemia, or at reperfusion. Mitochondrial function and ultrastructure were assessed and Western blots were performed.
Administration of SB203580 at any time point of I/R significantly attenuated the mitochondrial ultrastructure change, mitochondrial swelling, by increasing the absorbance at 540 nm (I/R control 0.42 ± 0.03; pretreatment 0.58 ± 0.04; during ischemia 0.49 ± 0.02; at reperfusion 0.51 ± 0.02, p < 0.05), similar to reactive oxygen species (ROS) generation (I/R control 1300 ± 48; pretreatment 1150 ± 30; during ischemia 1000 ± 50; at reperfusion 1050 ± 55, p < 0.05). Only SB203580 given before or during ischemia attenuated mitochondrial membrane depolarization (I/R control 0.78 ± 0.04; pretreatment 1.02 ± 0.03; during ischemia 1.05 ± 0.12, p < 0.05). In addition, pre-treatment of SB203580 significantly reduced the phosphorylation of p53, CREB, Bax, cytochrome c, and cleaved caspase 3.
The results from this study showed for the first time that p38 MAPK inhibition protects mitochondria from I/R injury.
[Show abstract][Hide abstract] ABSTRACT: Women have a lower incidence of cardiovascular diseases (CVD) than men at a similar age but have an increased incidence of CVD and metabolic syndrome after menopause, indicating the possible protective effects of estrogen on cardiometabolic function. Although obesity is known to increase CVD risks, its impact on the heart on estrogen deprivation is still inconclusive. We investigated the effects of obese-insulin resistance on cardiometabolic function in estrogen-deprived ovariectomized rats. Adult female ovariectomized (O) or sham (S)-operated rats randomly received either normal diet (ND, 19.77 % fat) or high-fat diet (HF, 57.60 % fat) (n = 6/group) for 12 weeks. The heart rate variability (HRV), left ventricular (LV) performance, cardiac autonomic balance, cardiac mitochondrial function, metabolic parameters, oxidative stress, and apoptotic markers were determined at 4, 8, and 12 weeks. Insulin resistance developed at week 8 in NDO, HFS, and HFO rats as indicated by increased plasma insulin and HOMA index. However, only HFO rats had elevated plasma cholesterol level at week 8, whereas HFS rats had showed elevation at week 12. In addition, only HFO rats had depressed HRV, impaired LV performance indicated by decreased fractional shortening (%FS) and cardiac mitochondrial dysfunction indicated by increased mitochondrial ROS level, mitochondrial depolarization and swelling, as early as week 8, whereas other groups exhibited them at week 12. Either estrogen deprivation or obesity alone may impair metabolic parameters, cardiac autonomic balance, and LV and mitochondrial function. However, an obese insulin-resistant condition further accelerated and aggravated the development of these cardiometabolic impairments in estrogen-deprived rats.
Age 04/2015; 37(2):9766. DOI:10.1007/s11357-015-9766-0 · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Adverse cardiac remodeling after myocardial infarction (MI) leads to progressive heart failure. Dipeptidyl peptidase-4 (DPP-4) inhibitor is a new antidiabetic drug that exerts cardioprotection. However, its role on cardiac function and remodeling in chronic MI is unclear. We hypothesized that DPP-4 inhibitor (vildagliptin) reduces adverse cardiac remodeling and improves cardiac function in chronic MI rats. These effects were also compared with enalapril and metformin. Male Wistar rats (n = 36) with chronic MI induced by left anterior descending coronary arterial ligation were divided into 6 groups to receive vehicle, vildagliptin (3 mg/kg/d), metformin (30 mg/kg/d), enalapril (10 mg/kg/d), combined metformin and enalapril, or combined vildagliptin and enalapril for 8 weeks. At the end of the study, plasma malondialdehyde, heart rate variability (HRV), left ventricular (LV) function, pathological and biochemical studies of cardiac remodeling were investigated. Our study demonstrated that chronic MI rats had increased oxidative stress levels, depressed HRV, and adverse cardiac remodeling indicated by cardiac fibrosis, and LV dysfunction. Treatment with vildagliptin and enalapril both significantly decreased oxidative stress, attenuated cardiac fibrosis, and improved HRV and LV function. We conclude that vildagliptin exerts similar cardioprotective effects as enalapril in attenuating oxidative stress and cardiac fibrosis and improving cardiac function in chronic MI rats. Metformin does not provide these benefits in this model. Moreover, addition of either metformin or vildagliptin to enalapril does not provide additional benefit in attenuating cardiac remodeling or improving LV function, compared to enalapril alone. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Although testosterone deficiency is associated with increased risks of heart disease, the benefits of testosterone therapy are controversial. Moreover, current understanding on the cardiac effect of testosterone during cardiac ischemia-reperfusion (I/R) periods is unclear. We tested the hypothesis that testosterone replacement attenuates the impairment of left ventricular (LV) function and heart rate variability (HRV), and reduces the infarct size and arrhythmias caused by I/R injury in orchiectomized (ORX) rats.
ORX or sham-operated male Wistar rats (n = 24) were randomly divided and received either testosterone (2 mg/kg, subcutaneously administered) or the vehicle for 8 weeks. The ejection fraction (EF) and HRV were determined at baseline and the 4th and 8th week. I/R was performed by left anterior descending coronary artery ligation for 30 minutes, followed by a 120-minute reperfusion. LV pressure, arrhythmia scores, infarct size and cardiac mitochondrial function were determined.
Prior to I/R, EF and HRV were impaired in the ORX group, but were restored in the testosterone-treated group. During I/R, arrhythmia scores and the infarct size were greater, and cardiac mitochondrial function was impaired, whereas the time to 1st VT/VF onset and the LV end-systolic pressure were decreased in the ORX group when compared to the sham group. Testosterone replacement attenuated the impairment of these parameters in ORX rats during I/R injury, but did not show any benefit or adverse effect in non-ORX rats.
Testosterone replacement restores cardiac function and autonomic regulation, and exerts cardioprotective effects during the I/R period via mitochondrial protection in ORX rats.
PLoS ONE 03/2015; 10(3):e0122503. DOI:10.1371/journal.pone.0122503 · 3.23 Impact Factor