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The study of single-cell mechanical properties helps detect and recognize abnormal cells and can provide a potential method for early diagnosis of fatal diseases. Although some cell models have been proposed to explain the mechanical response, most are based on specific experimental conditions and cannot be applied to various micro-operation conditions. Developing a general cell mechanical model for a variety of experimental conditions is of great significance. A mechanical model of a physiological microenvironment based on cardiomyocytes was constructed in vitro. The biomechanical properties of AC-16 cells in different axial positions were calculated using an inverted phase-contrast microscope. The mechanical parameters of rat cardiomyocytes were measured and analyzed using green fluorescent protein and a three-dimensional magnetic twisting instrument. Using the proposed model, we applied a series of experiments. The results showed that the square axis has the best inhibitory effect on the proliferation of AC-16 cells; with an increase in stimulation time, the inhibitory effect improves. In addition, high-frequency mechanical stimulation was more effective than the low frequency in inhibiting the proliferation of AC-16 cell lines. This kind of myocardial cell physiological microenvironment model can record real-time myocardial cell mechanics model under the mechanical feedback signal, it can repeat the myocardial cell in vitro mechanical signal, and can effectively represent the mechanical properties of myocardial cells. It provides a new research method to further explore myocardial cell responses to stimulation.

Protective effect of fluvastatin (Flu) on myocardial cells in mice with acute myocardial infarction (AMI) and the mechanism were explored. Forty C57B/L6 mice in similar physiological status were selected and randomly divided into sham operation (Sham) group (n=10), AMI group (n=10), Flu group (n=10) and Flu + Angiotensin II (Ang II) (Ang II) group (n=10). The pathological changes in heart tissues were detected via hematoxylin and eosin (H&E) staining, and apoptosis of myocardial cells was detected via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Moreover, the expression levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were determined using relevant kits, and the expression levels of Ras homolog gene family (Rho)-associated coiled-coil protein kinase 1 (ROCK1), ROCK2, B-cell lymphoma-2 (Bcl-2), Bcl-2 associated X protein (Bax) and nuclear factor-κB (NF-κB) in the infarction region were determined using Western blotting. The infarction area in mice in Flu group was significantly smaller than that in AMI group. In AMI group, the level of MDA in the serum and infarction tissues was remarkably higher than that in Sham group (P

We found that curcumin, a p300 histone acetyltransferase (HAT) inhibitor, prevents cardiac hypertrophy and systolic dysfunction at the stage of chronic heart failure in Dahl salt-sensitive rats (DS). It is unclear whether curcumin suppresses the development of hypertension-induced left ventricular hypertrophy (LVH) with a preserved ejection fraction. Therefore, in this study, we randomized DS (n = 16) and Dahl salt-resistant (DR) rats (n = 10) at 6 weeks of age to either curcumin or vehicle groups. These rats were fed a high-salt diet and orally administrated with 50 mg/kg/d curcumin or its vehicle for 6 weeks. Both curcumin and vehicle treatment groups exhibited similar degrees of high-salt diet-induced hypertension in DS rats. Curcumin significantly decreased hypertension-induced increase in posterior wall thickness and LV mass index, without affecting the systolic function. It also significantly reduced hypertension-induced increases in myocardial cell diameter, perivascular fibrosis and transcriptions of the hypertrophy-response gene. Moreover, it significantly attenuated the acetylation levels of GATA4 in the hearts of DS rats. A p300 HAT inhibitor, curcumin, suppresses the development of hypertension-induced LVH, without affecting blood pressure and systolic function. Therefore, curcumin may be used for the prevention of development of LVH in patients with hypertension.

Ginsenosides (20S)-Rg3 and (20R)-Rg3 are famous rare ginsenosides from red ginseng, and their configurations in C-20 are different. This study aimed to investigate the protective mechanism of ginsenosides (20S)-Rg3 and (20R)-Rg3 on H2 O2 -induced H9C2 cells and compare their activity. The results showed that the ginsenosides (20S)-Rg3 and (20R)-Rg3 could increase the cell activity and the levels of GSH-Px, SOD and CAT, and decrease activities of LDH, MDA and ROS. Further studies showed that ginsenosides (20S)-Rg3 and (20R)-Rg3 could prevent oxidative stress injury of H9C2 cells by H2 O2 through the Keap-1/Nrf2/HO-1 pathway. But the ML385 counteracts these effects. Interestingly, among these results, ginsenoside (20R)-Rg3 was superior to (20S)-Rg3, indicating that ginsenoside (20R)-Rg3 have a stronger effect of antioxidative stress. This study reflected that ginsenoside (20R)-Rg3 could be used as a potential Nrf2 activator and a safe effective Chinese herbal monomer in the treatment of cardiovascular disease.

Context: Myocardial cell death occurs within hours following the onset of myocardial ischaemia and its chief cause is atherosclerosis. There is a link between vitamin D3 deficiency and many cardiovascular risk factors.Objective: This study compared the effect of vitamin D3 on early biomarkers of myocardial injury, to that of atorvastatin.Methods: Diabetic hyperlipidaemia was induced in Wistar rats, which were divided into 3 groups: diabetic hyperlipidaemic control, diabetic hyperlipidaemic rats treated with atorvastatin and diabetic hyperlipidaemic rats treated with vitamin D3. Blood glucose, glycated haemoglobin and lipid profile were evaluated. Markers of myocardial injury were examined including cardiac troponin, heart fatty acid binding protein (HFABP) and C-terminal pro-endothelin-1 (CT-pro-ET-1).Results: Vitamin D3 and atorvastatin intake improved lipid profile and glucose homeostasis, and reduced levels of predictive biomarkers of myocardial injury.Conclusion: Vitamin D3 can be used in a suitable dose as a safe and protective candidate against myocardial injury.

Cardiac hypertrophy is characterized by an increase in myocardial cell volume and extracellular matrix production. Persistent cardiac hypertrophy can cause dilated cardiomyopathy, heart failure, and even death. Pinocembrin (5,7-dihydroxyflavanone) is a type of flavonoid, extracted from propolis, that has antimicrobial, antioxidant, antiinflammatory, and anticancer properties. The results of the present study showed that pretreatment of isoproterenol (ISO)-treated H9c2 cardiomyocytes with pinocembrin reduced the messenger RNA levels of hypertrophic markers, including atrial natriuretic factor and βeta-myosin heavy chain, and inflammatory cytokines, such as tumor necrosis factor-α, interleukin-6, interleukin-1β, and interferon-γ, and also inhibited p65 phosphorylation and nuclear factor-kappa B (NF-κB) translocation. In addition, the activity of IκBα, an inhibitor of NF-κB, was increased while that of caspase-3 was reduced under these conditions. These results indicate that pinocembrin may inhibit ISO-induced myocardial hypertrophy by attenuating the NF-κB signaling pathway.

Nigegladines A–C (1–3), three thymoquinone dimers, were isolated from the seeds of Nigella glandulifera. Racemic 1 possesses a unique tricyclo[5.4.0.12,6]dodecane carbon skeleton, and compounds 2 and 3 are two unusual diterpenoid alkaloids with indole cores. Their structures were determined by extensive spectroscopic analyses, and that of 1 was confirmed by single-crystal X-ray diffraction. Both (+)-1 and (−)-1 exhibited significant protective effects against hypoxia/reoxygenation-induced H9c2 myocardial cell injury.

Phytochemical investigation of the stem of Aralia chinensis yielded six new oleanane-type triterpene saponins named as congmujingnosides B-G (1–6). The new ones were elucidated on the basis of the chemical and spectroscopic analysis. Protective effects of compounds 1−6 were tested against H2O2-induced H9c2 cardiomyocyte injury, and the data showed that compounds 1 and 5 had significant cell-protective effects. No significant DPPH radical scavenging activity was observed for compounds 1−6.

In the present study, three new triterpenoids, 23-hydroxyurs-12, 18-dien-28-oic acid 3β-O-α-L-arabinopyranoside (1), 23-hydroxyurs-12, 18-dien-28-oic acid 3β-O-β-D-glucuronopyranoside-6-O-methyl ester (2), and urs-12, 18-dien-28-oic acid 3β-O-β-D-glucuronopyranoside-6-O-methyl ester (3), and a known triterpenoid, 3β-hydroxy-urs-2, 18-dien-28-oic acid (4, randialic acid B), were isolated from the aerial parts of Ilex cornuta. Their structures were identified by the spectroscopic analyses (IR, ESI-MS, HR-ESI-MS, and 1D and 2D NMR) and chemical reactions. Compound 4 showed significant cell-protective effects against H2O2-induced H9c2 cardiomyocyte injury. Compounds 1-4 did not show any significant DPPH radical scavenging activity.

Cell death is an important component of the pathophysiology of any disease. Myocardial disease is no exception. Understanding how and why cells die, particularly in the heart where cardiomyocyte regeneration is limited at best, becomes a critical area of study. Ferroptosis is a recently described form of nonapoptotic cell death. It is an iron-mediated form of cell death that occurs because of accumulation of lipid peroxidation products. Reactive oxygen species and iron-mediated phospholipid peroxidation is a hallmark of ferroptosis. To date, ferroptosis has been shown to be involved in cell death associated with Alzheimer’s disease, Huntington’s disease, cancer, Parkinson’s disease, and kidney degradation. Myocardial reperfusion injury is characterized by iron deposition as well as reactive oxygen species production. These conditions, therefore, favor the induction of ferroptosis. Currently there is no available treatment for reperfusion injury, which accounts for up to 50% of the final infarct size. This review will summarize the evidence that ferroptosis can induce cardiomyocyte death following reperfusion injury and the potential for this knowledge to open new therapeutic approaches for myocardial ischemia-reperfusion injury.

Retraction of ‘Knockdown of TUG1 aggravates hypoxia-induced myocardial cell injury via regulation of miR-144-3p/Notch1’ by Bo Zhu et al., RSC Adv., 2019, 9, 22931–22941, DOI: 10.1039/C9RA01311C.

INTRODUCTION: The objective of this study was to investigate the cardioprotective effects of a dodecafluoropentane (DDFP)-based perfluorocarbon emulsion (DDFPe) as an artificial carrier for oxygen delivery to ischemic myocardium, using (99m)Tc-duramycin SPECT imaging. METHODS: Rat hearts with Ischemia-reperfusion (I/R) was prepared by coronary ligation for 45-min followed by reperfusion. The feasibility of (99m)Tc-duramycin in detecting myocardial I/R injury and its kinetic profile were first verified in the ischemic hearts with 2-h reperfusion (n = 6). DDFPe (0.6 mL/kg) was intravenously administered at 10 min after coronary ligation in fifteen rats and saline was given in thirteen rats as controls. (99m)Tc-duramycin SPECT images were acquired in the DDFPe-treated hearts and saline controls at 2-h (DDFPe-2 h, n = 7 and Saline-2 h, n = 6) or 24-h (DDFPe-24 h, n = 8 and Saline-24 h, n = 7) of reperfusion. RESULTS: SPECT images, showing “hot-spot” (99m)Tc-duramycin uptake in the ischemic myocardium, exhibited significantly lower radioactive retention and smaller hot-spot size in the DDFPe-2 h and DDFPe-24 h hearts compared to controls. The infarcts in the Saline-24 h hearts extended significantly relative to measurements in the Saline-2 h. The extension of infarct size did not reach a statistical difference between the DDFPe-2 h and DDFPe-24 h hearts. Ex vivo measurement of (99m)Tc-duramycin activity (%ID/g) was lower in the ischemic area of DDFPe-2 h and DDFPe-24 h than that of the Saline-2 h and Saline-24 h hearts (P < 0.05). The area of injured myocardium, delineated by the uptake of (99m)Tc-duramycin, extended more substantially outside the infarct zone in the controls. CONCLUSIONS: Significant reduction in myocardial I/R injury, as assessed by (99m)Tc-duramycin cell death imaging and histopathological analysis, was induced by DDFPe treatment after acute myocardial ischemia. (99m)Tc-duramycin imaging can reveal myocardial cell death in ischemic hearts and may provide a tool for the non-invasive assessment of cardioprotective interventions.

Objective Long-term intensive training may led to ischemia oxygen reaction and increase the ROS. Astaxanthin, as the super antioxidant, was investigated to against anti-oxidative stress. By supplementing the astaxanthin, we wanted to observe if it can mediated Nrf2 reduces myocardial cell oxidative injury in rats after high intensity training of 6 weeks. Methods 7-week SD male rats were divided into 3 groups randomly: control group ( C group，n =10)，high intensity training group ( HT group，n = 15)，astaxanthin and high intensity training group (HTA group，n = 15) . The rats in HTA group were given with astaxanthin 20 mg /kg·d and in HT group were given with oil during the training day．The serum cTnI，myocardial apoptosis index, the expression of myocardial BAX, Bcl2, Nrf2, HO-1, myocardial MDA，SOD and T- AOC activity were measured 24 hours after the last training． Results After 6-week tranning of high intensity, compared with group C, the serum cTNI, myocardial apoptosis index, the expression of BAX and myocardial MDA were significantly higher in group HT(P

Myocardial ischemia-reperfusion (I/R) injury remains the leading risk factor of disability and mortality worldwide. In this study, the myocardial protective effect of eriodictyol (EDT) and the underlying mechanism in an ex vivo model of global myocardial I/R was investigated. After treatment with different concentrations of EDT, the decreased hemodynamic parameters induced by myocardial I/R injury were significantly attenuated by EDT. The elevated levels of IL-6, CRP, IL-8, and TNF-α were effectively reduced by EDT treatment. EDT also remarkably suppressed the levels of Bax and cleaved Caspase-3, and up-regulated the level of Bcl-2 in cardiac tissues from EDT-treated groups. Further studies showed that EDT could increase the levels of p-JAK2 and p-STAT3 in cardiac tissues. Meanwhile, treatment of AG490, a specific inhibitor of JAK2, abolished the protective effect of EDT on hemodynamic parameters, myocardial inflammation and myocardial cell apoptosis induced by I/R injury. These results demonstrated that EDT could protect against myocardial I/R injury through the activation of JAK2, providing a potential treatment with EDT during myocardial I/R injury.

Seven new triterpenoids (1–7), together with two known ones (8–9), were isolated from the aerial parts ofIlex cornuta. The leaves of I. cornuta are the major source of “Kudingcha”, a popular herbal tea consumed in China and other countries. The structures of compounds 1–7 were determined as 20-epi-urs-12,18-dien-28-oic acid 3β-O-α- l -arabinopyranoside (1), 20-epi-urs-12,18-dien-28-oic acid 2′-O-acetyl-3β-O-α- l -arabinopyranoside (2), 20-epi-urs-12,18-dien-28-oic acid 3β-O-β- d -glucuronopyranoside-6-O-methyl ester (3), 3β,23-dihydroxy-20-epi-urs-12,18-dien-28-oic acid (4), 23-hydroxy-20-epi-urs-12,18-dien-28-oic acid 3β-O-α- l -arabinopyranoside (5), 23-hydroxy-20-epi-urs-12,18-dien-28-oic acid 3β-O-β- d -glucuronic acid (6), 23-hydroxy-20-epi-urs-12,18-dien-28-oic acid 3β-O-β- d -glucuronopyranoside-6-O-methyl ester (7), on the basis of spectroscopic analyses (IR, ESI–MS, HR-ESI–MS, 1D and 2D NMR) and chemical reactions. Protective effects against H2O2-induced H9c2 cardiomyocyte injury were tested in vitro for compounds 1–9, and the data showed that compound 4 had significant cell-protective effect. Compounds 1-9 did not show significant DPPH radical scavenging activity.

Background: Compatibility of Radix Aconiti Carmichaeli and Liquorice is known to treat heart diseases such as heart failure and cardiac arrhythmias. This work answers the question that whether the active components (Aconitine, Liquiritin and Glycyrrhetinic Acid) of Radix Aconiti Carmichaeli and Liquorice could result in regulating intracellular calcium homeostasis and calcium cycling, and thereby verifies the therapeutic material basis. Materials and Methods: The myocardial cells were divided into twelve groups randomly as control group, Aconitine group, nine different dose groups that orthogonal combined with Aconitine, Liquiritin and Glycyrrhetinic Acid, and Verapamil group. The myocardial cellular survival rate and morphology were assessed. The expression of calcium regulation protein(RyR2、NCX1、DHPR-a1) in the myocardial cell by Western-blotting. Results: The results exhibited that Aconitine (120 uM) significantly damaged on myocardial cell, decreased the survival rate and expression of Na+/Ca2+ exchangers (NCX1) and dihydropteridine reducta-α1 (DHPR-a1), and increased the expression of ryanodine receptor type2 (RyR2) obviously. The compatibility groups (Aconitine, Liquiritin and Glycyrrhetinic Acid) all could against the damage on the myocardial cell by Aconitine at different levels. Conclusion: Aconitine with Liquiritin and Glycyrrhetinic Acid may regulate the expression of calcium-regulated proteins to protect myocardial cells from damage.

A new ferulic acid ester, 6-feruloyloxyhexanoic acid (1), was isolated along with 10 known ones (2–11), from the concentrated water extract of Rhodiola wallichiana var. cholaensis. Their chemical structures were elucidated on the basis of extensive spectroscopic methods including Two-dimensional nuclear magnetic resonance (2D NMR) experiments. Compound 3 was isolated from this plant for the first time. The protective effects against H2O2-induced myocardial cell injury in cultured H9c2 cells were also evaluated. Compounds 1, 5 and 7–11 provided significant protective effects on H2O2-induced H9c2 cells injury at the concentration of 25 μg/mL. And the protective effects of compound 1 was also investigated by the oxygen–glucose deprivation/reperfusion (OGD/R) tests.

Misfolded and aberrant proteins have been found to be associated with myocardial cell injury. Thus, increased clearance of misfolded or aggregated proteins via autophagy might be a potential option in preventing myocardial cell injury. Sevoflurane may ameliorate myocardial cell injury by affecting sirtuin 1- (SIRT1-) mediated autophagy. Rat models with myocardial cell injury were induced by limb ischemia reperfusion. The model rats received different treatments: sevoflurane, nicotinamide, and autophagy inhibitor 3-methyladenine (3-MA). Autophagy was observed by SEM. The levels of SIRT1 and microtubule-associated protein 1A/1B-light chain 3 (LC3) were measured. Present findings demonstrated that limb ischemia reperfusion induced autophagy. Sevoflurane increased the level of SIRT1, which deacetylated LC3 and further increased autophagic rates. On the other hand, the autophagy was inhibited by sevoflurane and or the inhibitors of SIRT1 and LC3. Present results demonstrated a novel molecular mechanism by which sevoflurane induced autophagy by increasing the level of SIRT1 and reducing the acetylation of LC3.

Background: Electronic cigarettes (ECs) have been marketed as an alternative-to-smoking habit. Besides chemical studies of the content of EC liquids or vapour, little research has been conducted on their in vitro effects. Smoking is an important risk factor for cardiovascular disease and cigarette smoke (CS) has well-established cytotoxic effects on myocardial cells. The purpose of this study was to evaluate the cytotoxic potential of the vapour of 20 EC liquid samples and a “base” liquid sample (50% glycerol and 50% propylene glycol, with no nicotine or flavourings) on cultured myocardial cells. Included were 4 samples produced by using cured tobacco leaves in order to extract the tobacco flavour. Methods: Cytotoxicity was tested according to the ISO 10993-5 standard. By activating an EC device at 3.7 volts (6.2 watts—all samples, including the “base” liquid) and at 4.5 volts (9.2 watts—four randomly selected samples), 200 mg of liquid evaporated and was extracted in 20 mL of culture medium. Cigarette smoke (CS) extract from three tobacco cigarettes was produced according to ISO 3308 method (2 s puffs of 35 mL volume, one puff every 60 s). The extracts, undiluted (100%) and in four dilutions (50%, 25%, 12.5%, and 6.25%), were applied to myocardial cells (H9c2); percent-viability was measured after 24 h incubation. According to ISO 10993-5, viability of 6.25% (viability: 76.9 ± 2.0% at 6.25%, 38.2 ± 0.5% at 12.5%, 3.1 ± 0.2% at 25%, 5.2 ± 0.8% at 50%, and 3.9 ± 0.2% at 100% extract concentration). Three EC extracts (produced by tobacco leaves) were cytotoxic at 100% and 50% extract concentrations (viability range: 2.2%–39.1% and 7.4%–66.9% respectively) and one (“Cinnamon-Cookies” flavour) was cytotoxic at 100% concentration only (viability: 64.8 ± 2.5%). Inhibitory concentration 50 was >3 times lower in CS extract compared to the worst-performing EC vapour extract. For EC extracts produced by high-voltage and energy, viability was reduced but no sample was cytotoxic according to ISO 10993-5 definition. Vapour produced by the “base” liquid was not cytotoxic at any extract concentration. Cell survival was not associated with nicotine concentration of EC liquids. Conclusions: This study indicates that some EC samples have cytotoxic properties on cultured cardiomyoblasts, associated with the production process and materials used in flavourings. However, all EC vapour extracts were significantly less cytotoxic compared to CS extract.

Introduction: The pathophysiology of potassium imbalances has been a dynamic area of medical research over the years. Controversy exists about the effectiveness and safety of various treatment strategies for hyperkalemia. Areas covered: The following discussion reviews potassium homeostasis, highlights common etiologies responsible for hyperkalemia and describes the associated clinical manifestations. An in-depth discussion about treatment strategies focuses on: i) stabilizing myocardial cell membranes, ii) enhancing cellular uptake of potassium and iii) the removal of excess potassium. The data for safety and efficacy of various therapies are reviewed. Expert opinion: Certain aspects of treating hyperkalemia remain controversial. Serum potassium is tightly regulated within a narrow range and precisely assessing the degree of risk associated with a given degree of hyperkalemia can be difficult. For this reason, it's important to individualize treatment strategies. Concerns regarding the risks of calcium a...

Magnesium is the fourth most abundant cation in the human body and is the second most prevalent cation in intracellular tissues. Myocardial cell action potentials are mediated by voltage-dependent Na+, K+, and Ca2+ channels which, when their function is altered, can lead to the genesis of cardiac dysrythmias. Magnesium regulates the movement of ions through these channels within myocardial tissues. The potential ability of magnesium supplementation to prevent and/or treat arrhythmias has been recognized in clinical medicine for years. This includes termination of torsade de pointes, prevention of post-operative atrial fibrillation, acute treatment of atrial fibrillation, and improving the efficacy and safety of antiarrhythmic drugs. Despite what is currently known about magnesium’s therapeutic potential, a number of limitations and gaps to the literature exist. This includes an unclear link between correction of intracellular magnesium concentrations and both mechanistic and clinical outcomes, small sample sizes, varying routes of administration and doses, as well as short follow-up periods. This review highlights these gaps and recommends areas of need for future research.

Objective: To study the injury effect and molecular mechanism of high glucose on myocardial cells. Methods: Myocardial cells H9c2 were cultured and divided into the control group treated with DMEM containing 5.5 mmol/L glucose, the high glucose group treated with DMEM containing 35 mmol/L glucose, and the N-acetylcysteine (NAC) group pre-treated with 1 000 μmol/L NAC and treated with DMEM containing 1 000 μmol/L NAC and 35 mmol/L glucose. The production of ROS and the expression of mitochondria pathway apoptosis molecules in cells as well as the contents of collagen and collagen metabolism molecules were measured. Results: After 8 h, 16 h and 24 h of treatment, ROS RFU as well as Bax, CytC, Caspase-3 and Caspase-9 protein expression in cells and Col-I, Col-III, PINP and PIIINP protein levels in culture medium of high glucose group were higher than those of control group, Bcl-2 protein expression were lower than those of control group, but CTX-I protein levels in culture medium were not significantly different from those of control group; after 24 h of treatment, Bax, CytC, Caspase-3 and Caspase-9 protein expression in cells as well as Col-I, Col-III, PINP and PIIINP protein levels in culture medium of NAC group were lower than those of high glucose group whereas Bcl-2 protein expression was higher than that of high glucose group. Conclusions: High glucose can induce myocardial cell apoptosis, increase collagen synthesis and accelerate interstitial fibrosis by increasing the production of reactive oxygen species.

The totality of functional cardiomyocytes and an intact cardiac progenitor cell pool are key players in the myocardial cell homeostasis. Perturbation of either one may compromise the structural and functional integrity of the heart and lead to heart failure. Reactive oxygen/nitrogen species (ROS/RNS) are important regulators of cardiomyocyte viability; more recently, the interrelation between ROS and progenitor cell behavior and fate has moved into the spotlight. Increasing evidence suggests not only that ROS participate in the regulation of cardiac progenitor cell survival but also that they likewise affect their functional properties in terms of self-proliferation and differentiation. The apparent dichotomy of ROS/RNS effects with their adaptive and regulatory character on the one hand and their maladaptive and damaging features on the other pose a great challenge in view of the therapeutic exploitation of their role in the regulation of the myocardial cell homeostasis. In this article, mechanisms and potential significance of ROS/RNS action in the regulation of the myocardial cell homeostasis, in particular with respect to the preservation of viable cardiomyocytes and the maintenance of a functional cardiac progenitor cell pool, will be discussed.

Whole-heart ischemia has been induced in isolated working rat heart. The distribution of the reduced coronary flow was even, as judged by 3H-antipyrine autoradiographs. Reducing the coronary flow resulted in myocardial ischemia, as indicated by a lowered tissue content of glycogen, ATP and creatine phosphate and accumulation of lactate. After a reperfusion period of 30 min there was a restoration of glycogen, ATP and creatine phosphate for hearts that were ischemic for 5 and 10 min, with a concomitant normalization of tissue lactate. Hearts that were ischemic for 30 min did not show restoration of high energy phosphates and glycogen. There was a leakage of ASAT, CK and LD in all groups of hearts, suggesting that a release of these enzymes does not necessarily indicate an irreversibly damaged myocardial cell.

Background Cells detect and adapt to hypoxic and nutritional stress through immediate transcriptional, translational and metabolic responses. The environmental effects of ischemia on chromatin nanostructure were investigated using single molecule localization microscopy of DNA binding dyes and of acetylated histones, by the sensitivity of chromatin to digestion with DNAseI, and by fluorescence recovery after photobleaching (FRAP) of core and linker histones. Results Short-term oxygen and nutrient deprivation of the cardiomyocyte cell line HL-1 induces a previously undescribed chromatin architecture, consisting of large, chromatin-sparse voids interspersed between DNA-dense hollow helicoid structures 40–700 nm in dimension. The chromatin compaction is reversible, and upon restitution of normoxia and nutrients, chromatin transiently adopts a more open structure than in untreated cells. The compacted state of chromatin reduces transcription, while the open chromatin structure induced upon recovery provokes a transitory increase in transcription. Digestion of chromatin with DNAseI confirms that oxygen and nutrient deprivation induces compaction of chromatin. Chromatin compaction is associated with depletion of ATP and redistribution of the polyamine pool into the nucleus. FRAP demonstrates that core histones are not displaced from compacted chromatin; however, the mobility of linker histone H1 is considerably reduced, to an extent that far exceeds the difference in histone H1 mobility between heterochromatin and euchromatin. Conclusions These studies exemplify the dynamic capacity of chromatin architecture to physically respond to environmental conditions, directly link cellular energy status to chromatin compaction and provide insight into the effect ischemia has on the nuclear architecture of cells. Electronic supplementary material The online version of this article (doi:10.1186/s13059-015-0802-2) contains supplementary material, which is available to authorized users.

We investigated whether acetyl salicylic acid (ASA) protects chicken myocardial cells from heat stress-mediated damage in vivo and whether the induction of Hsp27 expression is connected with this function. Pathological changes, damage-related enzyme levels, and Hsp27 expression were studied in chickens following heat stress (40 ± 1 °C for 0, 1, 2, 3, 5, 7, 10, 15, or 24 h, respectively) with or without ASA administration (1 mg/kg BW, 2 h prior). Appearance of pathological lesions such as degenerations and karyopyknosis as well as the myocardial damage-related enzyme activation indicated that heat stress causes considerable injury to the myocardial cells in vivo. Myocardial cell injury was most serious in chickens exposed to heat stress without prior ASA administration; meanwhile, ASA pretreatment acted protective function against high temperature-induced injury. Hsp27 expression was induced under all experimental conditions but was one-fold higher in the ASA-pretreated animals (0.3138 ± 0.0340 ng/mL) than in untreated animals (0.1437 ± 0.0476 ng/mL) 1 h after heat stress exposure, and such an increase was sustained over the length of the experiment. Our findings indicate that pretreatment with ASA protects chicken myocardial cells from acute heat stress in vivo with almost no obvious side effects, and this protection may involve an enhancement of Hsp27 expression. However, the detailed mechanisms underlying this effect require further investigation.

Membrane equations that describe sarcolemmal currents and ion transfer processes are important building blocks for theoretical studies of action potential propagation in cardiac tissue. Introduction of such ionic models into cellular and tissue networks allows analyses of passive contributions associated with tissue structure to be considered alongside active contributions from myocytes themselves in studies involving arrhythmia initiation, maintenance and termination. Maturation of contemporary membrane equations that attempt to replicate voltage clamp experiments from different species and tissue types with specific examples of modifications to extend those equations for simulations under conditions of rapid pacing, myocardial ischemia and remodeling following myocardial infarction are considered. Additionally, the integrating of membrane equations into models where coupling to represent current flow paths associated with the anisotropic tissue structure is described.

Myocardial ischemia-reperfusion injury involves activation of multiple cell types, including leukocytes and endothelial cells. The pursuant inflammation involves diminished nitric oxide production, influx of neutrophils, and myocardial cell injury. Gene-targeted animals provide important clues about the progression of this inflammatory cascade.

Five new triterpenoid saponins, 1-5, together with 10 known ones, 6-15 were isolated from the aerial parts of Ilex cornuta. The structures of compounds 1-5 were determined as 3β-O-α-L-arabinopyranosyl-19α,23-dihydroxy-20α-urs-12-en-28-oic acid 28-O-β-D-glucopyranosyl ester, 1; 3β-O-β-D-glucopyranosyl-(1→2)-α-L-arabinopyranosyl-19-hydroxy-20α-urs-12-en-28-oic acid 28-O-β-D-glucopyranosyl ester, 2; 19α,23-dihydroxyurs-12-en-28-oic acid 3β-O-β-D-glucuronopyranoside-6-O-methyl ester, 3; 19α,23-dihydroxyurs-12-en-28-oic acid 3β-O-[β-D-glucuronopyranoside-6-O-methyl ester]-28-O-β-D-glucopyranosyl ester, 4; and 3β-O-[α-L-arabinopyranosyl-(1→2)-β-D-glucuronic acid]-oleanolic acid 28-O-β-D-glucopyranosyl ester, 5, on the basis of spectroscopic analyses (IR, ESI-MS, HR-ESI-MS, 1D and 2D NMR) and chemical reactions. Protective effects of compounds 1-15 were tested against H2O2-induced H9c2 cardiomyocyte injury, and the data showed that compounds 1, 4, 6, and 13 had significant cell-protective effects. No significant DPPH radical scavenging activity was observed for compounds 1-15.

This study is aiming to find the signal transduction underlying calcium overloading caused cell apoptosis phenomenon post myocardial treatments. For the information of Wnt5a/frizzled-2 signal pathway in mammalian cardiac cells were hardly seen before, first we needed to confirm the gene and protein

BACKGROUND We have previously identified a phenomenon that we called vascular rhexis (VR) after coronary occlusion in mice. To explore its potential pathogenetic impact on the destruction of vessels described, its potential universality, and its characterization as a scaffolding for evaluating amelioration, we studied Sprague-Dawley rats from which multiple blood samples and robust tissue samples can be obtained. METHODS Rats were subjected to nonsustained coronary occlusion for 15 min, 1 h, 90 min, 3 h, or 4 h, followed by reperfusion. Soluble fractions of left ventricular (LV) homogenates were obtained 48 h later and assayed by western blotting for quantification of α-smooth muscle actin, diminution of which has been immunohistochemically shown to reflect delineation of VR. The functional integrity of vessel walls was assessed 24 h after induction of ischemia for selected intervals, followed by reperfusion using fluorescein isothiocyanate-tagged albumin injected through the tail vein 2 h before harvesting tissue. RESULTS Nonsustained coronary occlusion for 1 h initiated VR, evident 47 h after reperfusion; however, more brief ischemic insults did not. Loss of functional integrity was evident as judged from increases in extravasated fluorescein isothiocyanate-conjugated albumin in LV walls. CONCLUSION Because VR occurs early and may be ameliorated by interventions that can be initiated soon after the onset of nonsustained ischemia before myocardial cell death is substantial, its amelioration is an attractive target for diminution of late negative LV remodeling associated with the 'no reflow' phenomenon to which it can contribute.

Myocardial K+ currents function to control resting membrane potentials, the heights and durations of action potentials, and refractoriness and automaticity. They are important targets for the actions of transmitters and hormones or drugs known, or postulated, to modulate cardiac functioning. A variety of K+ currents that subserve these functions have now been identified in myocardial cells isolated from different species, as well as in cells isolated from different regions of the heart in the same species. These currents include the voltage-gated K+ types, such as the transient outward (Ito) and delayed rectifier (IK) currents, as well as the inwardly rectifying currents, IK1, IK(ACh), and IK(ATP). The physiological and functional properties of the various K+ currents/channels expressed in different myocardial cell types are the focus of this review. Advances made in cloning K+ channel subunits of the Kv, eag, Kir, and IsK families are discussed, and progress made in identifying the K+ channel subunits expressed in the mammalian myocardium is summarized. The relationships between the various cloned K+ channel subunits and the functional K+ channels characterized electrophysiologically in myocardial cells are explored.

Background: To observe the effects of salidroside on myocardial cell apoptosis in acute myocardial ischemia (AMI) rats and explore its possible molecular mechanisms. Methods: Sprague-Dawley (SD) rat models of AMI were established and randomized into salidroside high-dose (40 mg/kg) and low-dose (10 mg/kg) groups, AMI group, and sham group. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining was applied to analyze the myocardial cell apoptosis. Western blotting was used to determine the protein expressions of Bcl-2, Bax, Cytochrome c (Cyt-c), cleaved caspase-3, and cleaved caspase-9. Results: TUNEL staining showed that salidroside inhibited AMI-induced myocardial cell apoptosis in a dose-dependent manner. Moreover, compared with AMI group, the salidroside treatment groups had significantly increased protein expression of Bcl-2 and significantly decreased protein expression of Bax, Cyt-c, cleaved caspase-3, and cleaved caspase-9. Conclusions: Salidroside inhibits myocardial cell apoptosis during AMI, which may be achieved by inactivating the mitochondria-dependent pathway. This finding may provide labarotary evidence for the clinical application of salidroside in treating ischemic heart disease.

This study aimed to investigate a food effect on the bio-availability of modified-release (MR) trimetazidine tablets in 36 healthy volunteers. Trimetazidine, an anti-ischemic drug, protects the myocardial cell from the harmful effects of ischemia. The authors investigated the effect of being under a fasting or fed state at the time of drug intake on the bioavailability of trimetazidine 35-mg MR tablets in a randomized, open-label, crossover, 2-arm, 4-period, 2-sequence bioequivalence study design with a 14-day washout period. Plasma concentration of trimetazidine was assayed in timed samples with a validated high- performance liquid chromatography/mass selective detector that had a lower limit of quantification of 2.5 ng/mL. Test and reference formulations gave a mean trimetazidine Cmax of 63.26 ng/mL and 69.18 ng/mL for the fasting state and 64.19 ng/mL and 63.11 ng/mL for the fed state, respectively. The AUC0-tlast mean of trimetazidine was 726.31 ng·h/mL and 733.01 ng·h/mL for the fasting state and 706.40 ng·h/mL and 691.40 ng·h/mL for the fed state for test/reference formulations. There were no significant differences in pharmacokinetic parameters between the 2 formulations and the fasting/fed states. The authors showed that there is no food effect and no need for a 4-period study to evaluate the bioequivalence of trimetazidine MR tablets. © 2012 The Author(s).

Objectives High levels of soluble receptor for advanced glycation end products (sRAGE) have been shown to have an atheroprotective role; however, no data are available on this molecule in acute coronary syndromes (ACS). We evaluated sRAGE levels in patients with non-ST segment elevation ACS (NSTE-ACS) or with chronic stable angina. Methods We studied 265 patients, 190 of whom had NSTE-ACS and 75 had chronic stable angina. Results Plasma sRAGE values were comparable in the two groups (P=0.19). However, in the patients with NSTE-ACS, sRAGE levels were significantly higher in patients with cardiac troponin-I (cTnI) of more than or equal to 0.04 µg/l compared with those with cTnI of less than 0.04 µg/l [758 (493–1536 ) pg/ml vs. 454 (167–899) pg/ml; P=0.0037]. A significant correlation (r=0.323, P=0.0045) was found between sRAGE and cTnI levels in patients with NSTE-ACS. Conclusion Plasma sRAGE levels are elevated in patients with NSTE-ACS with positive cTnI, suggesting that they could be related to myocardial cell damage.

The myocardium can tolerate only relatively short periods of total myocardial ischemia without myocardial cell death. Following short ischemic periods, ischemic damage is reversible by reperfusion. However, with increasing duration and severity of ischemia, the damage inflicted to cardiomyocytes following reperfusion becomes irreversible. The combined pathologic events in the myocardium that follow a critical period of ischemia and leading to either reversible or irreversible damage to both cardiomyocytes and cardiac microvasculature is known as ischemia-reperfusion injury (Goldhaber and Weiss 1992).

A Comprehensive review of quantitative structure-activity relationship (QSAR) studies on antiarrhythmic agents is presented. From the discussion point of view, the antiarrhythmic agents have been put into two broad classes: specific and nonspecific. While the main members of the former class can be beta-adrenergic blocking agents (beta-blockers), any chemical that can act directly on the myocardial cell membrane, producing a cardiodepressant effect via changes in basic electrophysiological properties of the membrane, such as automaticity, excitability, conductivity, and refractoriness, has been put in the latter class. QSARs exhibit that the biological actions of a variety of drugs belonging to any class depend primarily on the lipophilic haracter of the molecule or substituents. Thus, the hydrophobic interaction is found to play a dominant role in the action of antiarrhythmic agents. In certain cases, the QSARs also exhibit the role of electronic parameters, suggesting that certain receptors may have electronic site also, permitting the drugs to involve in some electronic interactions, too.

Effects of various cardioactive agents and a water extract of the pilose antler of Cervus nippon var. mantchuricus on periodic beating of cultured myocardial cell sheets were examined by using an image analyzing system. Norepinephrine increased the beating rate and the beating amplitude, whereas digoxin and forskolin enlarged only the beating amplitude. Verapamil and propranolol decreased both the beating rate and the beating amplitude. The water extract of the pilose antler showed no remarkable effects in a standard medium (2.1 mM Ca2+). However, it significantly increased the beating amplitude when the beating was suppressed by replacement with a low calcium medium (0.5 mM Ca2+). A similar effect was found for 70% ethanol-soluble and -insoluble fractions of the extract.

Considerable evidence indicates that abnormalities in fatty acid and phospholipid metabolism are important in the pathogenesis of the membrane dysfunction that leads to irreversible myocardial cell injury during myocardial ischemia and related conditions. Membrane dysfunction is mediated by phospholipid degradation and by the accumulation of amphipathic lipid species, including free fatty acids, long-chain acyl-coenzyme A esters, long-chain acylcarnitines, and lipid peroxides. Accumulation of free arachidonic acid, a fatty acid normally stored in membrane phospholipids, is a sensitive indicator of phospholipid degradation. Ongoing work is aimed at defining mechanisms of the phospholipid alterations that appear to involve phospholipase-mediated phospholipid catabolism and impaired phospholipid synthesis.

This study was designed to investigate whether kits to measure circulating cardiac troponin-I (cTn-I) and cardiac troponin-T (cTn-T) can be used to determine myocardial cell damage in cattle with traumatic reticuloperitonitis (TRP). Twenty cattle with TRP were compared with 10 clinically healthy cattle. cTn-I and cTn-T were determined qualitatively and cTn-I was determined quantitatively; biochemical analyses were also performed on both groups. The mean serum concentrations of total protein, globulin, glucose and calcium, and the mean activities of creatine kinase MB, aspartate aminotransferase, lactate dehydrogenase and gamma-glutamyl transferase were higher in the cattle with TRP than in the control group. The cTn-I and cTn-T kits both gave positive results in three of the cattle with TRP and the quantitative measurement of cTn-I was positive in 11 of the TRP cases. Both tests were negative in the healthy cattle.

The coupled exchanger theory describes one of the central mechanisms of damage in the ischemic heart. The theory proposes that anaerobic glycolysis produces lactate and protons and that the protons can leave the cardiac cell on the cardiac Na+/H+ exchanger (NHE1). The subsequent rise in [Na+]i stimulates the cardiac Na+/Ca2+ exchanger (NCX) and results in an increase in [Ca2+]i which promotes myocardial cell damage. Although the general features of this theory are widely accepted, there is dispute about some aspects, specifically whether the NHE1 remains active during ischemia or not. We review the evidence on this issue and conclude that NHE1 is substantially inhibited during ischemia. This issue is central to the design of a clinical trial of NHE1 inhibitors in the treatment of human cardiac ischemia and the existing clinical trials are considered in this light.

The apoptosis of cardiac myocytes may play a role in the development of heart failure.1–3 Norepinephrine is one of factors activated in heart failure4 and can induce myocardial cell apoptosis in culture.5 However, it is unknown if α- and β-adrenergic pathways coordinately or differentially regulate apoptosis and if this apoptotic pathway utilizes common or cell type-specific apoptotic signals.

After injection of 6-[18F]fluorodopamine, thoracic positron emission tomographic scanning visualizes the sympathetic innervation of the heart. This report introduces a kinetic model that relates 6-[18F]fluorodopamine positron emission tomographic scanning results to specific aspects of cardiac sympathoneural function. Inputs were the 6-[18F]fluorodopamine concentration in arterial blood and the estimated contribution of circulating metabolites of 6-[18F]fluorodopamine. All of the three compartments in the model were intraneuronal. Two compartments corresponded to vesicles in sympathetic nerves, consistent with the "multiple vesicular pool" hypothesis from preclinical studies. The model successfully fit the empirical time-activity curve for myocardial 6-[18F]fluorodopamine-derived radioactivity and predicted correctly the effects of several neuropharmacological and physiological manipulations on the time-activity curve. Myocardial cell uptake of metabolites of 6-[18F]fluorodopamine from the circulation could explain an immediate peak of 6-[18F]fluorodopamine-derived radioactivity. The model seems useful in predicting effects of altered cardiac sympathetic function on time-activity curves for myocardial 6-[18F]fluorodopamine-derived radioactivity in humans.

The 1967 paper by Zimmerman et al. [1] is a sequel to one published in the previous year [2] in which Ariaen Zimmerman and Willem Hulsmann had described an artefact produced on an isolated rat heart preparation. It is exceptional that an artefact receives so much attention and is not forgotten three decades later. The observation they made is that, when an isolated heart is perfused for 2 min with a Ca2+ free, otherwise normal Krebs-Henseleit buffer and then with buffer containing a physiological Ca2+ concentration, it rapidly deteriorates. Massive enzyme release occurs and the heart becomes pale due to myoglobin loss. The 1967 paper demonstrates that these changes are accompanied with dramatic alterations of myocardial ultrastructure, i.e. membrane disruption, myofibrillar hypercontracture and mitochondrial damage. The discoverers named this impressive artefact ‘calcium paradox’. Since the original description this phenomenon has fascinated hundreds of researchers, with the highest research activity in the 1980s. This brief review is an attempt to explain 33 years after the original description the main reasons for this long-lasting fascination. It is not intended to duplicate previous scientific reviews [3–6]. In the 1970s and 1980s the pathophysiological importance of calcium for the heart was in the centre of scientific awareness. The calcium paradox was soon regarded as a paradigm in this area of research as it became clear that repletion of the once Ca2+ depleted heart leads to massive Ca2+ influx into the myocardial cells, a phenomenon also observed in other situations of severe myocardial cell injury. In particular, it was a widely accepted hypothesis that the calcium paradox represents a paradigm for the pathomechanism of severe ischemia-reperfusion injury. In the words of Albrecht Fleckenstein [7]: “Certainly, with restoring the blood perfusion of the previous ischemic region, an unlimited Ca2+ …