scholarly journals Vildagliptin and caloric restriction for cardioprotection in pre-diabetic rats

2017 ◽  
Vol 232 (2) ◽  
pp. 189-204 ◽  
Author(s):  
Pongpan Tanajak ◽  
Hiranya Pintana ◽  
Natthaphat Siri-Angkul ◽  
Juthamas Khamseekaew ◽  
Nattayaporn Apaijai ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Rate ◽  
Heart Rate Variability ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Cardiac Dysfunction ◽  
Metabolic Regulation ◽  
Left Ventricular ◽  
Lv Function ◽  
Insulin Resistant

Long-term high-fat diet (HFD) consumption causes cardiac dysfunction. Although calorie restriction (CR) has been shown to be useful in obesity, we hypothesized that combined CR with dipeptidyl peptidase-4 (DPP-4) inhibitor provides greater efficacy than monotherapy in attenuating cardiac dysfunction and metabolic impairment in HFD-induced obese-insulin resistant rats. Thirty male Wistar rats were divided into 2 groups to be fed on either a normal diet (ND, n = 6) or a HFD (n = 24) for 12 weeks. Then, HFD rats were divided into 4 subgroups (n = 6/subgroup) to receive just the vehicle, CR diet (60% of mean energy intake and changed to ND), vildagliptin (3 mg/kg/day) or combined CR and vildagliptin for 4 weeks. Metabolic parameters, heart rate variability (HRV), cardiac mitochondrial function, left ventricular (LV) and fibroblast growth factor (FGF) 21 signaling pathway were determined. Rats on a HFD developed insulin and FGF21 resistance, oxidative stress, cardiac mitochondrial dysfunction and impaired LV function. Rats on CR alone showed both decreased body weight and visceral fat accumulation, whereas vildagliptin did not alter these parameters. Rats in CR, vildagliptin and CR plus vildagliptin subgroups had improved insulin sensitivity and oxidative stress. However, vildagliptin improved heart rate variability (HRV), cardiac mitochondrial function and LV function better than the CR. Chronic HFD consumption leads to obese-insulin resistance and FGF21 resistance. Although CR is effective in improving metabolic regulation, vildagliptin provides greater efficacy in preventing cardiac dysfunction by improving anti-apoptosis and FGF21 signaling pathways and attenuating cardiac mitochondrial dysfunction in obese-insulin-resistant rats.

scholarly journals Testosterone deprivation accelerates cardiac dysfunction in obese male rats

2016 ◽  
Vol 229 (3) ◽  
pp. 209-220 ◽  
Author(s):  
Wanpitak Pongkan ◽  
Hiranya Pintana ◽  
Sivaporn Sivasinprasasn ◽  
Thidarat Jaiwongkam ◽  
Siriporn C Chattipakorn ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Mitochondrial Function ◽  
Cardiac Dysfunction ◽  
Left Ventricular ◽  
Normal Diet ◽  
Metabolic Parameters ◽  
Male Rats ◽  
Lv Function ◽  
Insulin Resistant ◽  
Aging Men

Low testosterone level is associated with increased risks of cardiovascular diseases. As obese-insulin-resistant condition could impair cardiac function and that the incidence of obesity is increased in aging men, a condition of testosterone deprivation could aggravate the cardiac dysfunction in obese-insulin-resistant subjects. However, the mechanism underlying this adverse effect is unclear. This study investigated the effects of obesity on metabolic parameters, heart rate variability (HRV), left ventricular (LV) function, and cardiac mitochondrial function in testosterone-deprived rats. Orchiectomized or sham-operated male Wistar rats (n=36per group) were randomly divided into groups and were given either a normal diet (ND, 19.77% of energy fat) or a high-fat diet (HFD, 57.60% of energy fat) for 12weeks. Metabolic parameters, HRV, LV function, and cardiac mitochondrial function were determined at 4, 8, and 12weeks after starting each feeding program. We found that insulin resistance was observed after 8weeks of the consumption of a HFD in both sham (HFS) and orchiectomized (HFO) rats. Neither the ND sham (NDS) group nor ND orchiectomized (NDO) rats developed insulin resistance. The development of depressed HRV, LV contractile dysfunction, and increased cardiac mitochondrial reactive oxygen species production was observed earlier in orchiectomized (NDO and HFO) rats at week 4, whereas HFS rats exhibited these impairments later at week 8. These findings suggest that testosterone deprivation accelerates the impairment of cardiac autonomic regulation and LV function via increased oxidative stress and impaired cardiac mitochondrial function in obese-orchiectomized male rats.

Abstract 15180: Myeloid Differentiation Factor 2 Inhibitor Improves Left Ventricular Function And Heart Rate Variability Via Attenuating Cardiac Mitochondrial Dysfunction In Pre-diabetic Rats

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Natticha Sumneang ◽  
Thura Thun Oo ◽  
thidarat jaiwongkam ◽  
Busarin Arunsak ◽  
Nattayaporn Apaijai ◽  
...  
Keyword(s):  
Heart Rate ◽  
Mitochondrial Dysfunction ◽  
Systemic Inflammation ◽  
Mitochondrial Function ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
Myeloid Differentiation ◽  
Lv Function ◽  
Lv Dysfunction ◽  
Myeloid Differentiation Factor

Introduction: Systemic inflammation is known as a key mediator of left ventricular (LV) dysfunction in pre-diabetic models including obese-insulin resistance. In obese rats, lipopolysaccharide activates myeloid differentiation factor 2 (MD2)/toll-like receptor 4 complex, leading to systemic inflammation. Previously, MD2 inhibitor L6H21 (20 mg/kg) was shown to effectively reduce systemic inflammation in obese mice. However, its potential benefits on the heart and the underlying mechanisms in pre-diabetic obese-insulin resistant rats are unknown. Hypothesis: L6H21 exerts cardiometabolic protection in pre-diabetic rats by improving LV function and heart rate variability (HRV) via reducing cardiac mitochondrial dysfunction. Methods: Male Wistar rats were fed either a normal diet (n=8) or high-fat diet (HFD, n=40) for 12 weeks. In HFD group, rats were divided into 5 groups (n=8/group): 1) vehicle (1% Na-carboxymethyl cellulose), 2) metformin (300 mg/kg, positive control), 3-5) L6H21 at 10, 20, and 40 mg/kg. After 4 weeks of treatments, LV function and HRV were examined. Heart tissue was assessed for mitochondrial function. Results: Pre-diabetic rats had impaired glucose tolerance, depressed HRV, and decreased LV ejection fraction (LVEF), indicating cardiac autonomic imbalance and LV dysfunction. Cardiac mitochondrial dysfunction was also observed, shown by increased mitochondrial ROS levels, mitochondrial depolarization, and mitochondrial swelling. Although L6H21 at 20 and 40 mg/kg improved insulin sensitivity, cardiac autonomic balance, LV function, and mitochondrial function, L6H21 at 40 mg/kg exerted the highest cardioprotective effects, compared to metformin, in pre-diabetic rats by restoring LV function, HRV, and cardiac mitochondrial function (Fig) . Conclusions: L6H21 exerted cardiometabolic protection in pre-diabetic rats by improving insulin sensitivity and cardiac mitochondrial function, leading to restoring LV function.

scholarly journals Necroptosis inhibitor directly reduced left ventricular dysfunction in obese-insulin resistant rats, independent of the metabolic status

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
N Apaijai ◽  
K Jinawong ◽  
K Singhanat ◽  
T Jaiwongkam ◽  
S Kerdphoo ◽  
...  
Keyword(s):  
Cell Death ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Left Ventricular ◽  
Metabolic Parameters ◽  
Lv Function ◽  
Cardiac Diseases ◽  
Funding Source ◽  
Insulin Resistant ◽  
Lv Dysfunction

Abstract Background The number of obese people is increasing globally. Our previous studies showed that chronic high-fat diet (HFD) consumption led to obesity with peripheral insulin resistance, which was associated with left ventricular (LV) dysfunction. Mechanistically, cardiac mitochondrial dysfunction and cell death are proposed as an underlying mechanism for LV dysfunction in obese subjects. Recently, necroptosis was defined as a novel cell death pathway, which can be found in various types of cardiac diseases such as myocardial ischaemia and heart failure. Pharmacological inhibition of necroptosis by necrostatin 1 (nec-1) provided the favorable outcomes to those cardiac diseases. However, the roles of necroptosis and the effects of nec-1 on the heart of obese-insulin resistant rats have never been investigated. Purpose We hypothesized that nec-1 attenuates LV dysfunction by reducing cardiac mitochondrial dysfunction, necroptosis, and apoptosis in obese-insulin resistant rats. Methods Male rats (n=32) were fed with normal diet (ND) or HFD for 12 weeks to induce obese-insulin resistance. At weeks 13, HFD-fed rats were assigned into 3 interventional groups (n=8/group) as follows: 1) HFD-fed rats treated with saline, 2) HFD-fed rats treated with nec-1 (1.65 mg/kg/day, subcutaneous injection), 3) HFD-fed rats treated with metformin (300 mg/kg/day, oral gavage feeding, served as a positive control). ND rats were treated with saline. Rats received their assigned interventions for additional 7 weeks. Blood pressure (BP), cardiac sympathovagal balance, and LV function were determined. At the end, the heart was excised to determine cardiac mitochondrial function including mitochondrial respiration, reactive oxygen species (ROS) levels, membrane potential changes, swelling, as well as apoptosis and necroptosis protein levels. Results HFD-fed rats had increased body weight, visceral fat deposition, hyperinsulinemia with euglycemia, and dyslipidemia. Moreover, HFD-fed rats had increased systolic and diastolic BP, reduced cardiac sympathovagal balance, and %LV ejection fraction (LVEF) (Fig. 1A). For mitochondrial function, respiratory control ratio was decreased, ROS levels were increased, along with mitochondrial membrane depolarization and swelling (Fig. 1B). Both necroptosis and apoptosis were observed in HFD-fed rats. Treatment with nec-1 reduced systolic and diastolic BP, cardiac sympathovagal imbalance, and increased %LVEF (Fig. 1A). Necroptosis and apoptosis were reduced, and all mitochondrial function parameters were improved in nec-1 treated rats (Fig. 1B). However, the metabolic parameters were not modified by nec-1. Treatment with metformin had similar benefits as nec-1 (Fig. 1), with additional improvement in metabolic parameters in HFD-fed rats. Conclusion Nec-1 directly improves LV function in obese-insulin resistant rats via attenuating cardiac mitochondrial dysfunction and cell death, independent of metabolic parameters. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Science and Technology Development Agency, Thailand Research Fund (TRF)

scholarly journals Transmural differences in respiratory capacity across the rat left ventricle in health, aging, and streptozotocin-induced diabetes mellitus: evidence that mitochondrial dysfunction begins in the subepicardium

2011 ◽  
Vol 300 (2) ◽  
pp. C246-C255 ◽  
Author(s):  
J. R. MacDonald ◽  
M. Oellermann ◽  
S. Rynbeck ◽  
G. Chang ◽  
K. Ruggiero ◽  
...  
Keyword(s):  
Heart Rate ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Streptozotocin Diabetes ◽  
Left Ventricular ◽  
Diabetic Rat ◽  
Rat Hearts ◽  
Myocardial Layers ◽  
Streptozotocin Induced Diabetes ◽  
Old Rats

In diabetic cardiomyopathy, ventricular dysfunction occurs in the absence of hypertension or atherosclerosis and is accompanied by altered myocardial substrate utilization and depressed mitochondrial respiration. It is not known if mitochondrial function differs across the left ventricular (LV) wall in diabetes. In the healthy heart, the inner subendocardial region demonstrates higher rates of blood flow, oxygen consumption, and ATP turnover compared with the outer subepicardial region, but published transmural respirometric measurements have not demonstrated differences. We aim to measure mitochondrial function in Wistar rat LV to determine the effects of age, streptozotocin-diabetes, and LV layer. High-resolution respirometry measured indexes of respiration in saponin-skinned fibers dissected from the LV subendocardium and subepicardium of 3-mo-old rats after 1 mo of streptozotocin-induced diabetes and 4-mo-old rats following 2 mo of diabetes. Heart rate and heartbeat duration were measured under isoflurane-anesthesia using a fetal-Doppler, and transmission electron microscopy was employed to observe ultrastructural differences. Heart rate decreased with age and diabetes, whereas heartbeat duration increased with diabetes. While there were no transmural respirational differences in young healthy rat hearts, both myocardial layers showed a respiratory depression with age (30–40%). In 1-mo diabetic rat hearts only subepicardial respiration was depressed, whereas after 2 mo diabetes, respiration in subendocardial and subepicardial layers was depressed and showed elevated leak (state 2) respiration. These data provide evidence that mitochondrial dysfunction is first detectable in the subepicardium of diabetic rat LV, whereas there are measureable changes in LV mitochondria after only 4 mo of aging.

scholarly journals Liraglutide protects cardiac function in diabetic rats through the PPARα pathway

2018 ◽  
Vol 38 (2) ◽  
Author(s):  
Qian Zhang ◽  
Xinhua Xiao ◽  
Jia Zheng ◽  
Ming Li ◽  
Miao Yu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Cardiac Dysfunction ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
Serum Adiponectin ◽  
Diabetic Rat ◽  
Lv Function ◽  
High Dose ◽  
And Oxidative Stress

Increasing evidence shows that diabetes causes cardiac dysfunction. We hypothesized that a glucagon-like peptide-1 (GLP-1) analog, liraglutide, would attenuate cardiac dysfunction in diabetic rats. A total of 24 Sprague–Dawley (SD) rats were divided into two groups fed either a normal diet (normal, n=6) or a high-fat diet (HFD, n=18) for 4 weeks. Then, the HFD rats were injected with streptozotocin (STZ) to create a diabetic rat model. Diabetic rats were divided into three subgroups receiving vehicle (diabetic, n=6), a low dose of liraglutide (Llirag, 0.2 mg/kg/day, n=6), or a high dose of liraglutide (Hlirag, 0.4 mg/kg/day, n=6). Metabolic parameters, systolic blood pressure (SBP), heart rate (HR), left ventricular (LV) function, and whole genome expression of the heart were determined. Diabetic rats developed insulin resistance, increased blood lipid levels and oxidative stress, and impaired LV function, serum adiponectin, nitric oxide (NO). Liraglutide improved insulin resistance, serum adiponectin, NO, HR, and LV function and reduced blood triglyceride (TG), total cholesterol (TC) levels, and oxidative stress. Moreover, liraglutide increased heart nuclear receptor subfamily 1, group H, member 3 (Nr1h3), peroxisome proliferator activated receptor (Ppar) α (Pparα), and Srebp expression and reduced diacylglycerol O-acyltransferase 1 (Dgat) and angiopoietin-like 3 (Angptl3) expression. Liraglutide prevented cardiac dysfunction by activating the PPARα pathway to inhibit Dgat expression and oxidative stress in diabetic rats.

In vivo TNF-α inhibition ameliorates cardiac mitochondrial dysfunction, oxidative stress, and apoptosis in experimental heart failure

2004 ◽  
Vol 287 (4) ◽  
pp. H1813-H1820 ◽  
Author(s):  
Gordon W. Moe ◽  
Jose Marin-Garcia ◽  
Andrea Konig ◽  
Michael Goldenthal ◽  
Xiangru Lu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Left Ventricular ◽  
Complex Iii ◽  
Dna Fragments ◽  
Respiratory Chain Enzyme ◽  
Tnf Α ◽  
Mitochondrial Respiratory

Heart failure is associated with increased myocardial expression of TNF-α. However, the role of TNF-α in the development of heart failure is not fully understood. In the present study, we investigated the contribution of TNF-α to myocardial mitochondrial dysfunction, oxidative stress, and apoptosis in a unique dog model of heart failure characterized by an activation of all of these pathological processes. Male mongrel dogs were randomly assigned ( n = 10 each) to 1) normal controls; 2) chronic pacing (250 beats/min for 4 wk) with concomitant administration of etanercept, a soluble p75 TNF receptor fusion protein, 0.5 mg/kg subcutaneously twice weekly; 3) chronic pacing with administration of saline vehicle. Mitochondrial function was assessed by left ventricular (LV) tissue mitochondrial respiratory enzyme activities. Oxidative stress was assessed with aldehyde levels, and apoptosis was quantified by photometric enzyme immunoassay for cytoplasmic histone-associated DNA fragments and terminal deoxynucleotide transferase-mediated nick-end labeling (TUNEL) assays. LV activity levels of mitochondrial respiratory chain enzyme complex III and V were reduced in the saline-treated dogs and restored either partially (complex III) or completely (complex V) in the etanercept-treated dogs. Aldehyde levels, DNA fragments, and TUNEL-positive cells were increased in the saline-treated dogs and normalized in etanercept-treated dogs. These changes were accompanied by an attenuation of LV dilatation and partial restoration of ejection fraction. Our data demonstrate that TNF-α contributes to progressive LV dysfunction in pacing-induced heart failure, mediated in part by a local impairment in mitochondrial function and increase in oxidative stress and myocyte apoptosis.

scholarly journals Metformin exerts cardioprotection via attenuating mitochondrial fission in cardiac ischaemia-reperfusion injury in rats

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Palee ◽  
L Higgins ◽  
T Leech ◽  
S.C Chattipakorn ◽  
N Chattipakorn
Keyword(s):  
Infarct Size ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fission ◽  
Left Ventricular ◽  
Control Group ◽  
Lv Function ◽  
Funding Source ◽  
Cardiac Ischaemia

Abstract Background Cardiac ischemia/reperfusion (I/R) injury following myocardial infarction reperfusion therapy is a phenomenon that results in further cardiomyocytes death and impaired cardiac contractility. Although metformin has been shown to exert cardioprotection in addition to glycemic control, its effect on cardiac I/R injury are still controversy, and the comparative doses of metformin in cardiac I/R injury have never been investigated. Purpose We hypothesized that metformin given acutely prior to cardiac ischaemia exerts cardioprotection in rats with cardiac I/R injury via attenuating cardiac mitochondrial dysfunction, leading to improved left ventricular (LV) function. Methods Forty Male Wistar rats were subjected to cardiac I/R injury. Four treatment groups were investigated. The first group received saline as a control group. The second to the fourth groups received metformin at 100, 200, and 400 mg/kg intravenously, respectively. During the I/R protocols, the LV function, arrhythmia score, and mortality rate were determined. At the end, the hearts were rapidly removed to determine infarct size, cardiac mitochondrial function, cardiac mitochondrial dynamics, and cardiac apoptosis. Results Metformin 200 mg/kg exerted the highest level of cardioprotection through the attenuated incidence of arrhythmia, decreased infarct size (Fig. 1), improved cardiac mitochondrial function, and decreased mitochondrial fission (Fig. 1) and cardiac apoptotic markers, leading to improved cardiac function during I/R injury. Although Metformin at all doses effectively decreased infarct size, improved cardiac mitochondrial function and LV function, Metformin at 200 mg/kg exerted the best efficacy (Fig. 1). Conclusions Metformin exerts cardioprotection by attenuating mitochondrial dysfunction and decreased mitochondrial fission, leading to decreased infarct size and ultimately improved LV function after acute cardiac I/R injury in rats. These findings also indicate the potential biphasic effects of metformin on infarct size which are dose-dependent. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Science and Technology Development Agency Thailand (NC), and Thailand Research Fund (SCC)

scholarly journals DPP-4 inhibitors improve cognition and brain mitochondrial function of insulin-resistant rats

2013 ◽  
Vol 218 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Hiranya Pintana ◽  
Nattayaporn Apaijai ◽  
Nipon Chattipakorn ◽  
Siriporn C Chattipakorn
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Dipeptidyl Peptidase 4 ◽  
Cognitive Behaviors ◽  
Insulin Resistant ◽  
Stress Levels ◽  
To Receive ◽  
Brain Mitochondrial Function

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 (HFD) 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 HFD-induced insulin-resistant rats have not yet been investigated. Sixty male Wistar rats were divided into two groups to receive either normal diet or HFD for 12 weeks. Rats in each group were then further divided into three treatment groups to receive either vehicle, vildagliptin (3 mg/kg per day), or sitagliptin (30 mg/kg per 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, the animals were killed and the brains were removed to investigate brain and hippocampal mitochondrial function as well as to determine oxidative stress levels. We demonstrated that both drugs significantly improved the metabolic parameters and decreased circulating and brain oxidative stress levels in HFD-induced insulin-resistant rats. In addition, both drugs completely prevented brain and hippocampal mitochondrial dysfunction and equally improved the learning behaviors impaired by the HFD. 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.

scholarly journals Obesity-Induced Heart Rate Variability Impairment and Decreased Systolic Function in Obese Male Dogs

Animals ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 1383
Author(s):  
Wanpitak Pongkan ◽  
Wannida Jitnapakarn ◽  
Warunee Phetnoi ◽  
Veerasak Punyapornwithaya ◽  
Chavalit Boonyapakorn
Keyword(s):  
Oxidative Stress ◽  
Heart Rate ◽  
Heart Rate Variability ◽  
Cardiovascular Diseases ◽  
Cardiac Function ◽  
Systolic Function ◽  
Left Ventricular ◽  
Normal Weight ◽  
Internal Diameter ◽  
Cardiac Wall

Obesity can induce cardiovascular diseases in both humans and animals. Heart rate variability (HRV) is an indicator of sympathovagal balance and is used to identify cardiovascular diseases in humans. However, HRV and cardiac function have rarely been investigated in obese dogs. This study investigated the effect of obesity on oxidative stress, HRV, and cardiac function in obese and non-obese dogs. The nine-scale body condition score (BCS) system was used to determine obesity. Thirty small breed dogs were divided into a normal weight group (n = 15) and an obese group (n = 15). All dogs underwent physical examination, plasma malondialdehyde (MDA) measurement, electrocardiography, echocardiography, and two hours of Holter monitoring. This study found that obese dogs had increased plasma MDA and sympathovagal imbalance, which was indicated by impaired time and frequency domains compared to normal weight dogs. Although cardiac function was within normal limits, the echocardiographic study found that the obese dogs had reduced cardiac wall thickness and lower systolic function, as indicated by a reduction in %ejection fraction, %fractional shortening, increased left ventricular (LV) internal diameter during systole, and LV end-systolic volume compared to normal weight dogs. This study concluded that obesity in dogs can induce increased plasma oxidative stress, impaired HRV, and reduced cardiac systolic function compared to non-obese dogs.

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