scholarly journals Cardioprotective Natural Compound Pinocembrin Attenuates Acute Ischemic Myocardial Injury via Enhancing Glycolysis

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Yanjun Zheng ◽  
Guoqing Wan ◽  
Bo Yang ◽  
Xuefeng Gu ◽  
Jingrong Lin
Keyword(s):  
Contractile Function ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Glycolytic Enzyme ◽  
Isolated Rat Heart ◽  
Cardiac Contractile Function ◽  
Direct Stimulation ◽  
Underlying Mechanisms

Purpose. Emerging evidence has shown that pinocembrin protects the myocardium from ischemic injury in animals. However, it is unknown whether it has cardioprotection when given at the onset of reperfusion. Also, mechanisms mediating the cardioprotective actions of pinocembrin were largely unknown. Thus, this study is aimed at investigating the effects of pinocembrin postconditioning on ischemia-reperfusion (I/R) injury and the underlying mechanisms. Methods. The in vivo mouse model of myocardial I/R injury, ex vivo isolated rat heart with global I/R, and in vitro hypoxia/reoxygenation (H/R) injury model for primary cardiomyocytes were used. Results. We found that pinocembrin postconditioning significantly reduced the infarct size and improved cardiac contractile function after acute myocardial I/R. Mechanically, in primary cardiomyocytes, we found that pinocembrin may confer protection in part via direct stimulation of cardiac glycolysis via promoting the expression of the glycolytic enzyme, PFKFB3. Besides, PFKFB3 inhibition abolished pinocembrin-induced glycolysis and protection in cardiomyocytes. More importantly, PFKFB3 knockdown via cardiotropic adeno-associated virus (AAV) abrogated cardioprotective effects of pinocembrin. Moreover, we demonstrated that HIF1α is a key transcription factor driving pinocembrin-induced PFKFB3 expression in cardiomyocytes. Conclusions. In conclusion, these results established that the acute cardioprotective benefits of pinocembrin are mediated in part via enhancing PFKFB3-mediated glycolysis via HIF1α, which may provide a new therapeutic target to impede the progression of myocardial I/R injury.

scholarly journals Cardiomyocyte-specific overexpression of an active form of Rac predisposes the heart to increased myocardial stunning and ischemia-reperfusion injury

2013 ◽  
Vol 304 (2) ◽  
pp. H294-H302 ◽  
Author(s):  
M. A. Hassan Talukder ◽  
Mohammad T. Elnakish ◽  
Fuchun Yang ◽  
Yoshinori Nishijima ◽  
Mazin A. Alhaj ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Ischemia Reperfusion Injury ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Active Form ◽  
Mutant Form ◽  
Cardiac Contractile Function ◽  
The Impact

The GTP-binding protein Rac regulates diverse cellular functions including activation of NADPH oxidase, a major source of superoxide production (O2·−). Rac1-mediated NADPH oxidase activation is increased after myocardial infarction (MI) and heart failure both in animals and humans; however, the impact of increased myocardial Rac on impending ischemia-reperfusion (I/R) is unknown. A novel transgenic mouse model with cardiac-specific overexpression of constitutively active mutant form of Zea maize Rac D (ZmRacD) gene has been reported with increased myocardial Rac-GTPase activity and O2·− generation. The goal of the present study was to determine signaling pathways related to increased myocardial ZmRacD and to what extent hearts with increased ZmRacD proteins are susceptible to I/R injury. The effect of myocardial I/R was examined in young adult wild-type (WT) and ZmRacD transgenic (TG) mice. In vitro reversible myocardial I/R for postischemic cardiac function and in vivo regional myocardial I/R for MI were performed. Following 20-min global ischemia and 45-min reperfusion, postischemic cardiac contractile function and heart rate were significantly reduced in TG hearts compared with WT hearts. Importantly, acute regional myocardial I/R (30-min ischemia and 24-h reperfusion) caused significantly larger MI in TG mice compared with WT mice. Western blot analysis of cardiac homogenates revealed that increased myocardial ZmRacD gene expression is associated with concomitant increased levels of NADPH oxidase subunit gp91phox, O2·−, and P21-activated kinase. Thus these findings provide direct evidence that increased levels of active myocardial Rac renders the heart susceptible to increased postischemic contractile dysfunction and MI following acute I/R.

Lipid peroxidation contributes to cardiac deficits after ischemia and reperfusion of the small bowel

1993 ◽  
Vol 264 (5) ◽  
pp. H1686-H1692 ◽  
Author(s):  
J. W. Horton ◽  
D. J. White
Keyword(s):  
Lipid Peroxidation ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Cardiac Contractile Function ◽  
Langendorff Preparation ◽  
Cardiac Contractile ◽  
Intestinal Ischemia Reperfusion

Our previous studies showed that intestinal ischemia-reperfusion (IR) impairs cardiac contractile function. The present study examined the contribution of oxygen free radicals and lipid peroxidation of cardiac cell membrane to cardiac dysfunction after intestinal IR in a rat model of superior mesenteric artery (SMA) occlusion (atraumatic clip for 20 min) and collateral arcade ligation. Controls were sham operated (group 1, n = 25). In group 2, 30 rats with SMA occlusion were killed 3-4 h after reperfusion without treatment. Aminosteroid (U-74389F), a pharmacological agent known to inhibit lipid peroxidation of membranes, was given 1 min before occlusion of the SMA (group 3, n = 19). All rats were killed 3-4 h after reperfusion of the ischemic intestine, and the hearts were harvested for in vitro assessment of cardiac function (Langendorff preparation). Cardiac contractile depression occurred in the untreated group as indicated by a fall in left ventricular pressure (from 76 +/- 3 to 64 +/- 3 mmHg, P = 0.01), maximum +dP/dt (from 1,830 +/- 60 to 1,577 +/- 64 mmHg/s, P = 0.05), and maximum -dP/dt (from 1,260 +/- 50 to 950 +/- 60 mmHg/s, P = 0.005). Lipid peroxidation of cardiac membranes occurred after untreated IR as indicated by the rise in cardiac malondialdehyde levels (MDA) (from 0.203 +/- 0.046 to 0.501 +/- 0.044 nM/mg protein, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Redox-Active Drug, MnTE-2-PyP5+, Prevents and Treats Cardiac Arrhythmias Preserving Heart Contractile Function

2020 ◽  
Vol 2020 ◽  
pp. 1-15 ◽  
Author(s):  
Andrezza M. Barbosa ◽  
José F. Sarmento-Neto ◽  
José E. R. Menezes Filho ◽  
Itamar C. G. Jesus ◽  
Diego S. Souza ◽  
...  
Keyword(s):  
Cardiac Arrhythmias ◽  
Contractile Function ◽  
Antiarrhythmic Effect ◽  
Cardiac Contractile Function ◽  
Rat Cardiomyocytes ◽  
Cell Contractility ◽  
Redox Active ◽  
Intracellular Ca

Background. Cardiomyopathies remain among the leading causes of death worldwide, despite all efforts and important advances in the development of cardiovascular therapeutics, demonstrating the need for new solutions. Herein, we describe the effects of the redox-active therapeutic Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin, AEOL10113, BMX-010 (MnTE-2-PyP5+), on rat heart as an entry to new strategies to circumvent cardiomyopathies. Methods. Wistar rats weighing 250-300 g were used in both in vitro and in vivo experiments, to analyze intracellular Ca2+ dynamics, L-type Ca2+ currents, Ca2+ spark frequency, intracellular reactive oxygen species (ROS) levels, and cardiomyocyte and cardiac contractility, in control and MnTE-2-PyP5+-treated cells, hearts, or animals. Cells and hearts were treated with 20 μM MnTE-2-PyP5+ and animals with 1 mg/kg, i.p. daily. Additionally, we performed electrocardiographic and echocardiographic analysis. Results. Using isolated rat cardiomyocytes, we observed that MnTE-2-PyP5+ reduced intracellular Ca2+ transient amplitude, without altering cell contractility. Whereas MnTE-2-PyP5+ did not alter basal ROS levels, it was efficient in modulating cardiomyocyte redox state under stress conditions; MnTE-2-PyP5+ reduced Ca2+ spark frequency and increased sarcoplasmic reticulum (SR) Ca2+ load. Accordingly, analysis of isolated perfused rat hearts showed that MnTE-2-PyP5+ preserves cardiac function, increases SR Ca2+ load, and reduces arrhythmia index, indicating an antiarrhythmic effect. In vivo experiments showed that MnTE-2-PyP5+ treatment increased Ca2+ transient, preserved cardiac ejection fraction, and reduced arrhythmia index and duration. MnTE-2-PyP5+ was effective both to prevent and to treat cardiac arrhythmias. Conclusion. MnTE-2-PyP5+ prevents and treats cardiac arrhythmias in rats. In contrast to most antiarrhythmic drugs, MnTE-2-PyP5+ preserves cardiac contractile function, arising, thus, as a prospective therapeutic for improvement of cardiac arrhythmia treatment.

Ischemic preconditioning of the whole heart confers protection on subsequently isolated ventricular myocytes

2008 ◽  
Vol 294 (1) ◽  
pp. H524-H531 ◽  
Author(s):  
Glenn C. Rodrigo ◽  
Nilesh J. Samani
Keyword(s):  
Ischemic Preconditioning ◽  
Ventricular Myocytes ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Isolated Cells ◽  
Cellular Models ◽  
Whole Heart ◽  
Intact Heart

Current cellular models of ischemic preconditioning (IPC) rely on inducing preconditioning in vitro and may not accurately represent complex pathways triggered by IPC in the intact heart. Here, we show that it is possible to precondition the intact heart and to subsequently isolate individual ventricular myocytes that retain the protection triggered by IPC. Myocytes isolated from Langendorff-perfused hearts preconditioned with three cycles of ischemia-reperfusion were exposed to metabolic inhibition and reenergization. Injury was assessed from induction of hypercontracture and loss of Ca2+ homeostasis and contractile function. IPC induced an immediate window of protection in isolated myocytes, with 64.3 ± 7.6% of IPC myocytes recovering Ca2+ homeostasis compared with 16.9 ± 2.4% of control myocytes ( P < 0.01). Similarly, 64.1 ± 5.9% of IPC myocytes recovered contractile function compared with 15.3 ± 2.2% of control myocytes ( P < 0.01). Protection was prevented by the presence of 0.5 mM 5-hydroxydecanoate during the preconditioning stimulus. This early protection disappeared after 6 h, but a second window of protection developed 24 h after preconditioning, with 54.9 ± 4.7% of preconditioned myocytes recovering Ca2+ homeostasis compared with 12.6 ± 2.9% of control myocytes ( P < 0.01). These data show that “true” IPC of the heart confers both windows of protection in the isolated myocytes, with a similar temporal relationship to in vivo preconditioning of the whole heart. The model should allow future studies in isolated cells of the protective mechanisms induced by true ischemia.

scholarly journals Detrimental effects of thyroid hormone analog DITPA in the mouse heart: increased mortality with in vivo acute myocardial ischemia-reperfusion

2011 ◽  
Vol 300 (2) ◽  
pp. H702-H711 ◽  
Author(s):  
M. A. Hassan Talukder ◽  
Fuchun Yang ◽  
Yoshinori Nishijima ◽  
Chun-An Chen ◽  
Lin Xie ◽  
...  
Keyword(s):  
Heart Rate ◽  
Thyroid Hormone ◽  
Myocardial Ischemia ◽  
Contractile Function ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Cardiac Metabolism ◽  
Mouse Heart ◽  
Myocardial Ischemia Reperfusion

There is emerging evidence that treatment with thyroid hormone (TH) can improve postischemic cardiac function. 3,5-Diiodothyropropionic acid (DITPA), a TH analog, has been proposed to be a safer therapeutic agent than TH because of its negligible effects on cardiac metabolism and heart rate. However, conflicting results have been reported for the cardiac effects of DITPA. Importantly, recent clinical trials demonstrated no symptomatic benefit in patients with DITPA despite some improved hemodynamic and metabolic parameters. To address these issues, dose-dependent effects of DITPA were investigated in mice for baseline cardiovascular effects and postischemic myocardial function and/or salvage. Mice were treated with subcutaneous DITPA at 0.937, 1.875, 3.75, or 7.5 mg·kg−1·day−1 for 7 days, and the results were compared with untreated mice for ex vivo and/or in vivo myocardial ischemia-reperfusion (I/R). DITPA had no effects on baseline body temperature, body weight, or heart rate; however, it mildly increased blood pressure. In isolated hearts, baseline contractile function was significantly impaired in DITPA-pretreated mice; however, postischemic recovery was comparable between untreated and DITPA-treated groups. In vivo baseline cardiac parameters were significantly affected by DITPA, with increased ventricular dimensions and decreased contractile function. Importantly, DITPA-treated mice demonstrated high prevalence of fatal cardiac rhythm abnormalities during in vivo ischemia and/or reperfusion. There were no improvements in myocardial infarction and postischemic fractional shortening with DITPA. Myocardial sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), phospholamban (PLB), and heat shock protein (HSP) levels remained unchanged with DITPA treatment. Thus DITPA administration impairs baseline cardiac parameters in mice and can be fatal during in vivo acute myocardial I/R.

scholarly journals Organization of β-adrenoceptor signaling compartments by sympathetic innervation of cardiac myocytes

2007 ◽  
Vol 176 (4) ◽  
pp. 521-533 ◽  
Author(s):  
Olga G. Shcherbakova ◽  
Carl M. Hurt ◽  
Yang Xiang ◽  
Mark L. Dell'Acqua ◽  
Qi Zhang ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Cardiac Myocytes ◽  
Contractile Function ◽  
Sympathetic Neurons ◽  
Sympathetic Innervation ◽  
Cardiac Contractile Function ◽  
Cardiac Contractile ◽  
Specific Regulation

The sympathetic nervous system regulates cardiac function through the activation of adrenergic receptors (ARs). β1 and β2ARs are the primary sympathetic receptors in the heart and play different roles in regulating cardiac contractile function and remodeling in response to injury. In this study, we examine the targeting and trafficking of β1 and β2ARs at cardiac sympathetic synapses in vitro. Sympathetic neurons form functional synapses with neonatal cardiac myocytes in culture. The myocyte membrane develops into specialized zones that surround contacting axons and contain accumulations of the scaffold proteins SAP97 and AKAP79/150 but are deficient in caveolin-3. The β1ARs are enriched within these zones, whereas β2ARs are excluded from them after stimulation of neuronal activity. The results indicate that specialized signaling domains are organized in cardiac myocytes at sites of contact with sympathetic neurons and that these domains are likely to play a role in the subtype-specific regulation of cardiac function by β1 and β2ARs in vivo.

Abstract 12636: Pro-Atrial Natriuretic Peptide: A Novel Guanylyl Cyclase-A Receptor Activator Which Goes Beyond Carperitide and Nesiritide

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Tomoko Ichiki ◽  
Brenda K Huntley ◽  
Ingrid A Andersen ◽  
S Jeson Sangaralingham ◽  
Gail J Harty ◽  
...  
Keyword(s):  
Guanylyl Cyclase ◽  
Half Life ◽  
Ex Vivo ◽  
Normal Subjects ◽  
Hek293 Cells ◽  
Direct Stimulation ◽  
Hek Cells ◽  
Renal Tubular

Introduction: ProANP is a 108 amino acid (AA) prohormone which is produced in the atria and processed to the mature 28 AA ANP which activates the guanylyl cyclase receptor-A (GC-A) and its second messenger cGMP. ProANP is found in the human circulation but its bioavailability is undefined. Hypothesis: ProANP represents a novel cardiac peptide with more sustained natriuretic actions than either carperitide (ANP) or nesiritide (BNP). ProANP itself can activate GC-A in vitro and the proANP can be processed in human serum from normals and in patients with heart failure (HF). Methods: We examined the in vivo cardiorenal actions of proANP compared to ANP, BNP, or placebo in normal canines (667 pmol/kg, n=5/group). We determined cGMP activation of proANP, ANP and BNP in GC-A expressing HEK293 cells. ProANP processing and degradation was also defined in serum from normal subjects (n=13) and patients with HF (n=14) ex vivo. Results: ProANP had significantly greater diuretic and natriuretic properties with increased renal blood flow and sustained renal tubular actions compared to ANP or BNP in canines. ProANP also resulted in greater and more prolonged cardiac unloading than ANP, and much less hypotensive effects than BNP. The plasma half-life of proANP was 4.5 times longer than ANP and 3.8 times longer than BNP. ProANP itself stimulated cGMP generation in GC-A expressing HEK cells which was equal to ANP. ProANP was processed to ANP in fresh serum from normals as well as HF patients ex vivo and the processed peptide activated cGMP in GC-A expressing HEK cells. Conclusions: ProANP represents a novel GC-A activator with a longer half-life and greater natriuresis and diuresis than ANP and BNP and less hypotensive effects than BNP. The bioactivity of exogenous proANP may be through direct stimulation of GC-A, as well as through processing into ANP, as proANP is processed in the circulation of both normal and HF. As proANP circulates in the human circulation, proANP may represent a key circulating hormone in cardiorenal and blood pressure homeostasis as well as a potential innovative therapeutic beyond ANP (carperitide) or BNP (nesiritide) for cardiorenal diseases including HF.

The role of microRNA in modulating myocardial ischemia-reperfusion injury

2011 ◽  
Vol 43 (10) ◽  
pp. 534-542 ◽  
Author(s):  
Yumei Ye ◽  
Jose R. Perez-Polo ◽  
Jinqiao Qian ◽  
Yochai Birnbaum
Keyword(s):  
Heart Disease ◽  
Reperfusion Injury ◽  
Fas Ligand ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Therapeutic Targets ◽  
In Vitro Models

MicroRNAs (miRNAs) are small (∼22 nt) noncoding single-stranded RNA molecules that downregulate gene expression. Studies have shown that miRNAs control diverse aspects of heart disease, including hypertrophy, remodeling, heart failure, and arrhythmia. Recently, several studies have suggested that miRNAs contribute to ischemia-reperfusion injury by altering key signaling elements, thus making them potential therapeutic targets. By altering the expression of various key elements in cell survival and apoptosis [such as phosphoinositide 3-kinase (PI3K), phosphatase and tensin homolog deleted on chromosome 10 (PTEN), Bcl-2, Mcl-1, heat shock protein (HSP)60, HSP70, HSP20, programmed cell death 4 (Pdcd4), LRRFIP1, Fas ligand (FasL), Sirt-1, etc.], miRNAs alter the response to ischemia-reperfusion injury. Studies using various in vivo, ex vivo, and in vitro models have suggested the possible involvement of miR-1, miR-21, miR-29, miR-92a, miR-133, miR-199a, and miR-320 in ischemia-reperfusion injury and/or remodeling after myocardial infarction. Thus miRNAs could be potential therapeutic targets for the treatment of heart disease. Inhibiting miRNAs by antisense strategies or pharmacological approaches is likely to emerge as an alternative and safe method for conferring short- and intermediate-term protection against ischemia-reperfusion injury.

scholarly journals DKK3 (Dikkopf-3) Transdifferentiates Fibroblasts Into Functional Endothelial Cells—Brief Report

2019 ◽  
Vol 39 (4) ◽  
pp. 765-773 ◽  
Author(s):  
Ting Chen ◽  
Eirini Karamariti ◽  
Xuechong Hong ◽  
Jiacheng Deng ◽  
Yutao Wu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Ex Vivo ◽  
Human Fibroblasts ◽  
Defined Media ◽  
Mesenchymal To Epithelial Transition ◽  
Potential Strategy ◽  
Underlying Mechanisms ◽  
Endothelial Growth Factor

Objective— To determine the role of a cytokine-like protein DKK3 (dikkopf-3) in directly transdifferentiating fibroblasts into endothelial cells (ECs) and the underlying mechanisms. Approach and Results— DKK3 overexpression in human fibroblasts under defined conditions for 4 days led to a notable change in cell morphology and progenitor gene expression. It was revealed that these cells went through mesenchymal-to-epithelial transition and subsequently expressed KDR (kinase insert domain receptor) at high levels. Further culture in EC defined media led to differentiation of these progenitors into functional ECs capable of angiogenesis both in vitro and in vivo, which was regulated by the VEGF (vascular endothelial growth factor)/miR (microRNA)-125a-5p/Stat3 (signal transducer and activator of transcription factor 3) axis. More importantly, fibroblast-derived ECs showed the ability to form a patent endothelium-like monolayer in tissue-engineered vascular grafts ex vivo. Conclusions— These data demonstrate that DKK3 is capable of directly differentiating human fibroblasts to functional ECs under defined media and provides a novel potential strategy for endothelial regeneration.

Atrial contractile dysfunction, fibrosis, and arrhythmias in a mouse model of cardiomyopathy secondary to cardiac-specific overexpression of tumor necrosis factor-α

2005 ◽  
Vol 289 (4) ◽  
pp. H1456-H1467 ◽  
Author(s):  
Samir Saba ◽  
Andrzej M. Janczewski ◽  
Linda C. Baker ◽  
Vladimir Shusterman ◽  
Erdal C. Gursoy ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mouse Model ◽  
Contractile Function ◽  
Ex Vivo ◽  
Atrial Arrhythmias ◽  
Programmed Stimulation ◽  
Atrial Muscle ◽  
Tnf Α

Transgenic mice overexpressing the inflammatory cytokine TNF-α in the heart develop a progressive heart failure syndrome characterized by biventricular dilatation, decreased ejection fraction, decreased survival compared with non-transgenic littermates, and earlier pathology in males. TNF-α mice (TNF1.6) develop atrial arrhythmias on ambulatory telemetry monitoring that worsen with age and are more severe in males. We performed in vivo electrophysiological testing in transgenic and control mice, ex vivo optical mapping of voltage in the atria of isolated perfused TNF1.6 hearts, and in vitro studies on isolated atrial muscle and cells to study the mechanisms that lead to the spontaneous arrhythmias. Programmed stimulation induces atrial arrhythmias ( n = 8/32) in TNF1.6 but not in control mice ( n = 0/37), with a higher inducibility in males. In the isolated perfused hearts, programmed stimulation with single extra beats elicits reentrant atrial arrhythmias ( n = 6/6) in TNF1.6 but not control hearts due to slow heterogeneous conduction of the premature beats. Lowering extracellular Ca2+ normalizes conduction and prevents the arrhythmias. Atrial muscle and cells from TNF1.6 compared with control mice exhibit increased collagen deposition, decreased contractile function, and abnormal systolic and diastolic Ca2+ handling. Thus abnormalities in action potential propagation and Ca2+ handling contribute to the initiation of atrial arrhythmias in this mouse model of heart failure.

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