High-fat, low-carbohydrate diet promotes arrhythmic death and increases myocardial ischemia-reperfusion injury in rats

High-fat, low-carbohydrate diets (HFLCD) are often eaten by humans for a variety of reasons, but the effects of such diets on the heart are incompletely understood. We evaluated the impact of HFLCD on myocardial ischemia/reperfusion (I/R) using an in vivo model of left anterior descending coronary artery ligation. Sprague-Dawley rats (300 g) were fed HFLCD (60% calories fat, 30% protein, 10% carbohydrate) or control (CONT; 16% fat, 19% protein, 65% carbohydrate) diet for 2 wk and then underwent open chest I/R. At baseline (preischemia), diet did not affect left ventricular (LV) systolic and diastolic function. Oil red O staining revealed presence of lipid in the heart with HFLCD but not in CONT. Following I/R, recovery of LV function was decreased in HFLCD. HFLCD hearts exhibited decreased ATP synthase and increased uncoupling protein-3 gene and protein expression. HFLCD downregulated mitochondrial fusion proteins and upregulated fission proteins and store-operated Ca2+ channel proteins. HFLCD led to increased death during I/R; 6 of 22 CONT rats and 16 of 26 HFLCD rats died due to ventricular arrhythmias and hemodynamic shock. In surviving rats, HFLCD led to larger infarct size. We concluded that in vivo HFLCD does not affect nonischemic LV function but leads to greater myocardial injury during I/R, with increased risk of death by pump failure and ventricular arrhythmias, which might be associated with altered cardiac energetics, mitochondrial fission/fusion dynamics, and store-operated Ca2+ channel expression.

Download Full-text

Cardioprotection of electroacupuncture against myocardial ischemia-reperfusion injury by modulation of cardiac norepinephrine release

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00030.2012 ◽

2012 ◽

Vol 302 (9) ◽

pp. H1818-H1825 ◽

Cited By ~ 34

Author(s):

Wei Zhou ◽

Yoshihiro Ko ◽

Peyman Benharash ◽

Kentaro Yamakawa ◽

Sunny Patel ◽

...

Keyword(s):

Myocardial Ischemia ◽

Infarct Size ◽

Ventricular Arrhythmias ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Sham Acupuncture ◽

Left Ventricular ◽

Lv Function ◽

Cardioprotective Effects ◽

Myocardial Ischemia Reperfusion

Augmentation of cardiac sympathetic tone during myocardial ischemia has been shown to increase myocardial O2 demand and infarct size as well as induce arrhythmias. We have previously demonstrated that electroacupuncture (EA) inhibits the visceral sympathoexcitatory cardiovascular reflex. The purpose of this study was to determine the effects of EA on left ventricular (LV) function, O2 demand, infarct size, arrhythmogenesis, and in vivo cardiac norepinephrine (NE) release in a myocardial ischemia-reperfusion model. Anesthetized rabbits ( n = 36) underwent 30 min of left anterior descending coronary artery occlusion followed by 90 min of reperfusion. We evaluated myocardial O2 demand, infarct size, ventricular arrhythmias, and myocardial NE release using microdialysis under the following experimental conditions: 1) untreated, 2) EA at P5–6 acupoints, 3) sham acupuncture, 4) EA with pretreatment with naloxone (a nonselective opioid receptor antagonist), 5) EA with pretreatment with chelerythrine (a nonselective PKC inhibitor), and 6) EA with pretreatment with both naloxone and chelerythrine. Compared with the untreated and sham acupuncture groups, EA resulted in decreased O2 demand, myocardial NE concentration, and infarct size. Furthermore, the degree of ST segment elevation and severity of LV dysfunction and ventricular arrhythmias were all significantly decreased ( P < 0.05). The cardioprotective effects of EA were partially blocked by pretreatment with naloxone or chelerythrine alone and completely blocked by pretreatment with both naloxone and chelerythrine. These results suggest that the cardioprotective effects of EA against myocardial ischemia-reperfusion are mediated through inhibition of the cardiac sympathetic nervous system as well as opioid and PKC-dependent pathways.

Download Full-text

IMPACT OF HIGH-FAT, LOW-CARBOHYDRATE DIET ON MYOCARDIAL ISCHEMIA / INFARCTION: AN IN VIVO STUDY

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(12)60542-7 ◽

2012 ◽

Vol 59 (13) ◽

pp. E541

Author(s):

Steven G. Lloyd ◽

Jian Liu ◽

Peipei Wang

Keyword(s):

Myocardial Ischemia ◽

In Vivo Study ◽

High Fat ◽

Carbohydrate Diet ◽

Low Carbohydrate Diet ◽

Low Carbohydrate

Download Full-text

A peptide inhibitor of c-Jun NH2-terminal kinase reduces myocardial ischemia-reperfusion injury and infarct size in vivo

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01117.2006 ◽

2007 ◽

Vol 292 (4) ◽

pp. H1828-H1835 ◽

Cited By ~ 71

Author(s):

Giuseppina Milano ◽

Sandrine Morel ◽

Christophe Bonny ◽

Michele Samaja ◽

Ludwig K. von Segesser ◽

...

Keyword(s):

Myocardial Ischemia ◽

Infarct Size ◽

P38 Mapk ◽

Ischemia Reperfusion ◽

Mapk Signaling ◽

Left Ventricular ◽

Mitogen Activated Protein Kinase ◽

Peptide Inhibitor ◽

Myocardial Ischemia Reperfusion

The c-Jun NH2-terminal kinase (JNK) pathway of the mitogen-activated protein kinase (MAPK) signaling cascade regulates cell function and survival after stress stimulation. Equally robust studies reported dichotomous results suggesting both protective and detrimental effects of JNK during myocardial ischemia-reperfusion (I/R). The lack of a highly specific JNK inhibitor contributed to this controversy. We recently developed a cell-penetrating, protease-resistant peptide inhibitor of JNK, d-JNKI-1. Here we report on the effects of d-JNKI-1 in myocardial I/R. d-JNKI-1 was tested in isolated-perfused adult rat hearts. Increased activation of JNK, p38-MAPK, and extracellular signal-regulated kinase-1/2 (ERK1/2), as assessed by kinase assays and Western blotting, occurred during I/R. d-JNKI-1 delivered before onset of ischemia prevented the increase in JNK activity while not affecting ERK1/2 and p38-MAPK activation. JNK inhibition reduced ischemic injury, as manifested by increased time to contracture ( P < 0.05) and decreased left ventricular end-diastolic pressure during ischemia ( P < 0.01), and enhanced posthypoxic recovery of systolic and diastolic function ( P < 0.01). d-JNKI-1 reduced mitochondrial cytochrome- c release, caspase-3 activation, and the number of apoptotic cells determined by terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling ( P < 0.05), indicating suppression of the mitochondrial machinery of apoptosis. d-JNKI-1 delivered at the time of reperfusion did not improve functional recovery but still prevented apoptosis. In vivo, d-JNKI-1 reduced infarct size after coronary artery occlusion and reperfusion by ∼50% ( P < 0.01). In conclusion, d-JNKI-1 is an important compound that can be used in preclinical models to investigate the role of JNK signaling in vivo. Inhibition of JNK during I/R is cardioprotective in anesthetized rats in vivo.

Download Full-text

Impact of high-fat, low-carbohydrate diet on myocardial substrate oxidation, insulin sensitivity, and cardiac function after ischemia-reperfusion

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00809.2015 ◽

2016 ◽

Vol 311 (1) ◽

pp. H1-H10 ◽

Cited By ~ 6

Author(s):

Jian Liu ◽

Peipei Wang ◽

Samuel L. Douglas ◽

Joshua M. Tate ◽

Simon Sham ◽

...

Keyword(s):

Insulin Sensitivity ◽

Cardiac Function ◽

Ischemia Reperfusion ◽

Substrate Oxidation ◽

Left Ventricular ◽

High Fat ◽

Carbohydrate Diet ◽

Low Carbohydrate Diet ◽

Low Carbohydrate ◽

Myocardial Substrate

High-fat, low-carbohydrate Diet (HFLCD) impairs the myocardial response to ischemia-reperfusion, but the underlying mechanisms remain elusive. We sought to determine the magnitude of diet-induced alterations in intrinsic properties of the myocardium (including insulin sensitivity and substrate oxidation) and circulating substrate and insulin differences resulting from diet, leading to this impaired response. Rats were fed HFLCD (60% kcal from fat/30% protein/10% carbohydrate) or control diet (CONT) (16%/19%/65%) for 2 wk. Isolated hearts underwent global low-flow ischemia followed by reperfusion (I/R). Carbon-13 NMR spectroscopy was used to determine myocardial substrate TCA cycle entry. Myocardial insulin sensitivity was assessed as dose-response of Akt phosphorylation. There was a significant effect of HFLCD and I/R with both these factors leading to an increase in free fatty acid (FFA) oxidation and a decrease in carbohydrate or ketone oxidation. Following I/R, HFLCD led to decreased ketone and increased FFA oxidation; the recovery of left ventricular (LV) function was decreased in HFLCD and was negatively correlated with FFA oxidation and positively associated with ketone oxidation. HFLCD also resulted in reduced insulin sensitivity. Under physiologic ranges, there were no direct effects of buffer insulin and ketone levels on oxidation of any substrate and recovery of cardiac function after I/R. An insulin-ketone interaction exists for myocardial substrate oxidation characteristics. We conclude that the impaired recovery of function after ischemia-reperfusion with HFLCD is largely due to intrinsic diet effects on myocardial properties, rather than to diet effect on circulating insulin or substrate levels.

Download Full-text

Inhaled nitric oxide decreases infarction size and improves left ventricular function in a murine model of myocardial ischemia-reperfusion injury

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01172.2005 ◽

2006 ◽

Vol 291 (1) ◽

pp. H379-H384 ◽

Cited By ~ 93

Author(s):

Ryuji Hataishi ◽

Ana Clara Rodrigues ◽

Tomas G. Neilan ◽

John G. Morgan ◽

Emmanuel Buys ◽

...

Keyword(s):

Nitric Oxide ◽

At Risk ◽

Myocardial Ischemia ◽

Murine Model ◽

Ischemia Reperfusion ◽

Left Ventricular ◽

Lv Function ◽

Area At Risk ◽

Myocardial Ischemia Reperfusion ◽

Hemodynamic Measurements

To learn whether nitric oxide (NO) inhalation can decrease myocardial ischemia-reperfusion (I/R) injury, we studied a murine model of myocardial infarction (MI). Anesthetized mice underwent left anterior descending coronary artery ligation for 30, 60, or 120 min followed by reperfusion. Mice breathed NO beginning 20 min before reperfusion and continuing thereafter for 24 h. MI size and area at risk were measured, and left ventricular (LV) function was evaluated using echocardiography and invasive hemodynamic measurements. Inhalation of 40 or 80 ppm, but not 20 ppm, NO decreased the ratio of MI size to area at risk. NO inhalation improved LV systolic function, as assessed by echocardiography 24 h after reperfusion, and systolic and diastolic function, as evaluated by hemodynamic measurements 72 h after reperfusion. Myocardial neutrophil infiltration was reduced in mice breathing NO, and neutrophil depletion prevented inhaled NO from reducing myocardial I/R injury. NO inhalation increased arterial nitrite levels but did not change myocardial cGMP levels. Breathing 40 or 80 ppm NO markedly and significantly decreased MI size and improved LV function after ischemia and reperfusion in mice. NO inhalation may represent a novel method to salvage myocardium at risk of I/R injury.

Download Full-text

Abstract P321: Chronic Central Nervous System Leptin Infusion Increases Cardiomyocyte Mitochondrial Function And Biogenesis And Improves Cardiac Function After Ischemia-reperfusion Injury.

Circulation Research ◽

10.1161/res.129.suppl_1.p321 ◽

2021 ◽

Vol 129 (Suppl_1) ◽

Author(s):

Ana Carolina M Omoto ◽

Jussara Do Carmo ◽

Xuan Li ◽

Zhen Wang ◽

Alan J Mouton ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Myocardial Ischemia ◽

Cardiac Function ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Left Ventricular ◽

Lv Function ◽

Myocardial Ischemia Reperfusion

Mitochondrial (MT) dysfunction plays an important role in the pathophysiology of myocardial ischemia/reperfusion injury (I/R). We recently showed that leptin, via its actions in the central nervous system (CNS), improves left ventricular (LV) function in a model of heart failure induced by permanent ligation of the left anterior descending coronary artery (LAD). In the present study, we examined if the CNS effects of leptin protect against myocardial ischemia/reperfusion (I/R) injury, and whether chronic intracerebroventricular (ICV) leptin infusion increases MT function and biogenesis in the non-infarcted area of the LV that is at risk but still viable. Male Wistar rats were instrumented with an ICV cannula in the brain lateral ventricle. After recovery and baseline assessment of cardiac function by echocardiography (ECHO), myocardial I/R was induced by temporary (60 min) ligation of the LAD. Vehicle (saline, 0.5 μL/hr) or leptin (0.62 μg/day) was infused chronically for 28 days starting 20 min after reperfusion using osmotic minipumps connected to the ICV cannula. ECHO assessment of cardiac function was performed every week. At the end of week 4, +dP/dt max and Tau were accessed by LV catheterization. Hearts were then collected for evaluation of MT function in isolated cardiac fibers using Oroboros oxygraphy-2k respirometer. ICV leptin treatment improved systolic and diastolic function as evidenced by increased ejection fraction 4 weeks after I/R (46±3 vs. 26±3 %), stroke volume (353±19 vs. 193±27 μL), +dP/dt max (10387±1686 vs. 5022±442 mmHg/s) and reduced Tau (6.5±0.3 vs. 8±0.3 ms) when compared with vehicle-treated rats. In addition, ICV leptin infusion significantly increased ATP-linked respiration (55±3 vs. 39±1 %), reduced proton leak (45±3 vs. 61±1 %), and improved MT reserve capacity (42±5 vs. 27±2 %). Improved MT function was associated with increased MT Complex I- mediated respiration (47±6 vs. 26±1 pmolO 2 /s - mg). ICV leptin treatment also increased PGC1 α protein expression and COX3 gene expression, indicating enhanced MT biogenesis. These results demonstrate that chronic ICV leptin infusion improves cardiac function following I/R injury and suggests that leptin’s CNS-mediated cardioprotective effects may involve improved myocardial MT function and biogenesis.

Download Full-text

iPLA2β Contributes to ER Stress-Induced Apoptosis during Myocardial Ischemia/Reperfusion Injury

Cells ◽

10.3390/cells10061446 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1446

Author(s):

Tingting Jin ◽

Jun Lin ◽

Yingchao Gong ◽

Xukun Bi ◽

Shasha Hu ◽

...

Keyword(s):

Cell Death ◽

Heart Disease ◽

Myocardial Ischemia ◽

Ischemic Heart Disease ◽

Er Stress ◽

Ischemia Reperfusion ◽

Myocardial Ischemia Reperfusion ◽

Induced Apoptosis

Both calcium-independent phospholipase A2 beta (iPLA2β) and endoplasmic reticulum (ER) stress regulate important pathophysiological processes including inflammation, calcium homeostasis and apoptosis. However, their roles in ischemic heart disease are poorly understood. Here, we show that the expression of iPLA2β is increased during myocardial ischemia/reperfusion (I/R) injury, concomitant with the induction of ER stress and the upregulation of cell death. We further show that the levels of iPLA2β in serum collected from acute myocardial infarction (AMI) patients and in samples collected from both in vivo and in vitro I/R injury models are significantly elevated. Further, iPLA2β knockout mice and siRNA mediated iPLA2β knockdown are employed to evaluate the ER stress and cell apoptosis during I/R injury. Additionally, cell surface protein biotinylation and immunofluorescence assays are used to trace and locate iPLA2β. Our data demonstrate the increase of iPLA2β augments ER stress and enhances cardiomyocyte apoptosis during I/R injury in vitro and in vivo. Inhibition of iPLA2β ameliorates ER stress and decreases cell death. Mechanistically, iPLA2β promotes ER stress and apoptosis by translocating to ER upon myocardial I/R injury. Together, our study suggests iPLA2β contributes to ER stress-induced apoptosis during myocardial I/R injury, which may serve as a potential therapeutic target against ischemic heart disease.

Download Full-text

MicroRNA-330-5p inhibits NLRP3 inflammasome-mediated myocardial ischemia-reperfusion injury by targeting TIM3

European Heart Journal ◽

10.1093/ehjci/ehaa946.3648 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

W Zuo ◽

R Tian ◽

Q Chen ◽

L Wang ◽

Q Gu ◽

...

Keyword(s):

Myocardial Ischemia ◽

Reperfusion Injury ◽

Nlrp3 Inflammasome ◽

Ischemia Reperfusion Injury ◽

Infarct Volume ◽

Ischemia Reperfusion ◽

Left Ventricular ◽

Myocardial Ischemia Reperfusion Injury ◽

Myocardial Ischemia Reperfusion

Abstract Background Myocardial ischemia-reperfusion injury (MIRI) is one of the leading causes of human death. Nod-like receptor protein-3 (NLRP3) inflammasome signaling pathway involved in the pathogenesis of MIRI. However, the upstream regulating mechanisms of NLRP3 at molecular level remains unknown. Purpose This study investigated the role of microRNA330-5p (miR-330-5p) in NLRP3 inflammasome-mediated MIRI and the associated mechanism. Methods Mice underwent 45 min occlusion of the left anterior descending coronary artery followed by different times of reperfusion. Myocardial miR-330-5p expression was examined by quantitative polymerase chain reaction (PCR), and miR-330-5p antagomir and agomir were used to regulate miR-330-5p expression. To evaluate the role of miR-330-5p in MIRI, Evans Blue (EB)/2, 3, 5-triphenyltetrazolium chloride (TTC) staining, echocardiography, and immunoblotting were used to assess infarct volume, cardiac function, and NLRP3 inflammasome activation, respectively. Further, in vitro myocardial ischemia-reperfusion model was established in cardiomyocytes (H9C2 cell line). A luciferase binding assay was used to examine whether miR-330-5p directly bound to T-cell immunoglobulin domain and mucin domain-containing molecule-3 (TIM3). Finally, the role of miR-330-5p/TIM3 axis in regulating apoptosis and NLRP3 inflammasome formation were evaluated using flow cytometry assay and immunofluorescence staining. Results Compared to the model group, inhibiting miR-330-5p significantly aggravated MIRI resulting in increased infarct volume (58.09±6.39% vs. 37.82±8.86%, P<0.01) and more severe cardiac dysfunction (left ventricular ejection fraction [LVEF] 12.77%±6.07% vs. 27.44%±4.47%, P<0.01; left ventricular end-diastolic volume [LVEDV] 147.18±25.82 vs. 101.31±33.20, P<0.05; left ventricular end-systolic volume [LVESV] 129.11±30.17 vs. 74.29±28.54, P<0.05). Moreover, inhibiting miR-330-5p significantly increased the levels of NLRP3 inflammasome related proteins including caspase-1 (0.80±0.083 vs. 0.60±0.062, P<0.05), interleukin (IL)-1β (0.87±0.053 vs. 0.79±0.083, P<0.05), IL-18 (0.52±0.063 vs. 0.49±0.098, P<0.05) and tissue necrosis factor (TNF)-α (1.47±0.17 vs. 1.03±0.11, P<0.05). Furthermore, TIM3 was confirmed as a potential target of miR-330-5p. As predicted, suppression of TIM3 by small interfering RNA (siRNA) ameliorated the anti-miR-330-5p-mediated apoptosis of cardiomyocytes and activation of NLRP3 inflammasome signaling pathway (Figure 1). Conclusion Overall, our study indicated that miR-330-5p/TIM3 axis involved in the regulating mechanism of NLRP3 inflammasome-mediated myocardial ischemia-reperfusion injury. Figure 1 Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): National Natural Science Foundation of China Grants

Download Full-text