Myocardial Tissue Injury Research Articles

Coptisine alleviates ischemia/reperfusion-induced myocardial damage by regulating apoptosis-related proteins

Coptisine is an alkaloid with many biological functions, but studies on its mechanism in myocardial ischemia-reperfusion (I/R) injury are less reported. Hypoxia–reoxygenation (H/R) -treated cardiomyocytes injury and I/R-induced myocardial tissues damage were created in rat models with or without the pre-treatment of coptisine. The proliferation and apoptosis of cardiomyocytes and changes of myocardial tissues were observed after the pre-treatment of coptisine. The pre-treatment of coptisine promoted cell proliferation and inhibited apoptosis of H/R-injured cardiomyocytes, and alleviated the myocardial tissue injury caused by I/R in rats. Moreover, coptisine promoted the expressions of anti-apoptotic proteins and inhibited the expressions of pro-apoptotic proteins in vivo and in vitro. The current study found that coptisine had protective effects on I/R-induced myocardial damage, which may provide a new insight into the treatment of I/R.

Abnormal ECG in a Structurally Normal Heart

A 63-year-old woman presented with an abnormal electrocardiogram (ECG) triggered by a murmur on physical examination. The ECG showed low atrial ectopic rhythm at rate 46 bpm with diffuse abnormal T wave and prolonged QTc at 546 milliseconds (Fig. 1). She was completely asymptomatic. She had a history of hypertension with no other cardiovascular risk factors along with normal laboratory values. Coronary angiography revealed normal coronary arteries and normal left ventricle (LV) contractility. An ECG demonstrated normal LV size and systolic function, and cardiac magnetic resonance imaging (MRI) revealed normal LV size and function with no evidence of myocardial edema, necrosis, fibrosis, or acute myocardial tissue injury of the LV. Right ventricular size and systolic function were also normal. The main differential diagnosis of inverted T waves includes ischemia, hypertrophy, and intracranial abnormalities. As such, we did proceed with computed tomography head that showed evidence of 3.7 cm mass most consistent with planum sphenoidale meningioma. A subsequent MRI confirmed a broad-based dural mass measuring 34 × 35 × 27 mm centred in the anterior cranial fossa with a significant superolateral mass effect on the overlying bilateral frontal lobes with vasogenic edema (Fig. 2, A and B ). Dynamic ECG changes have been observed in patients with subarachnoid haemorrhage or stroke. Cerebrovascular masses may also increase sympathetic activity and a-adrenergic stimulation with subsequent ECG changes such as ST-segment depression, profound T-wave inversion, and QTc interval prolongation.1Hersch C. Electrocardiographic changes in head injuries.Circulation. 1961; 23: 853-860Crossref PubMed Scopus (86) Google Scholar, 2Kopikkar S. Baranchuk A. Guzman J.C. Morillo C.A. Stroke and ventricular arrhythmias.Int J Cardiol. 2013; 168: 653-659Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar, 3Kukla P. Jastrzębski M. Kurdzielewicz W. et al.Dynamic ECG changes in a patient with subarachnoid haemorrhage.Kardiol Pol. 2014; 72: 473-475Crossref PubMed Scopus (1) Google Scholar Our patient presented with ECG changes secondary to the meningioma mass effect. The patient was referred to neurosurgery and is planned for surgical excision of the mass.

Red blood cell-derived semaphorin 7A promotes thrombo-inflammation in myocardial ischemia-reperfusion injury through platelet GPIb

Myocardial ischemia is one of the leading health problems worldwide. Therapy consists of the restitution of coronary perfusion which is followed by myocardial inflammation. Platelet–neutrophil interaction is a crucial process during inflammation, yet its consequences are not fully understood. Here, we show that platelet–neutrophil complexes (PNCs) are increased in patients with acute myocardial infarction and that this is associated with increased levels of neuronal guidance protein semaphorin 7A (SEMA7A). To investigate this further, we injected WT animals with Sema7a and found increased infarct size with increased numbers of PNCs. Experiments in genetically modified animals identify Sema7a on red blood cells to be crucial for this condition. Further studies revealed that Sema7a interacts with the platelet receptor glycoprotein Ib (GPIb). Treatment with anti-Sema7a antibody protected from myocardial tissue injury. In summary, we show that Sema7a binds to platelet GPIb and enhances platelet thrombo-inflammatory activity, aggravating post-ischemic myocardial tissue injury.

Fisetin protects against cardiac cell death through reduction of ROS production and caspases activity

Myocardial infarction (MI) is a leading cause of death worldwide. Reperfusion is considered as an optimal therapy following cardiac ischemia. However, the promotion of a rapid elevation of O2 levels in ischemic cells produces high amounts of reactive oxygen species (ROS) leading to myocardial tissue injury. This phenomenon is called ischemia reperfusion injury (IRI). We aimed at identifying new and effective compounds to treat MI and minimize IRI. We previously studied heart regeneration following myocardial injury in zebrafish and described each step of the regeneration process, from the day of injury until complete recovery, in terms of transcriptional responses. Here, we mined the data and performed a deep in silico analysis to identify drugs highly likely to induce cardiac regeneration. Fisetin was identified as the top candidate. We validated its effects in an in vitro model of MI/IRI in mammalian cardiac cells. Fisetin enhances viability of rat cardiomyocytes following hypoxia/starvation – reoxygenation. It inhibits apoptosis, decreases ROS generation and caspase activation and protects from DNA damage. Interestingly, fisetin also activates genes involved in cell proliferation. Fisetin is thus a highly promising candidate drug with clinical potential to protect from ischemic damage following MI and to overcome IRI.

Vitamin D3 intake as modulator for the early biomarkers of myocardial tissue injury in diabetic hyperlipidaemic rats

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.

MiR-4674 regulates angiogenesis in tissue injury by targeting p38K signaling in endothelial cells.

Neoangiogenesis is critical for tissue repair in response to injury such as myocardial ischemia or dermal wound healing. MicroRNAs are small noncoding RNAs and important regulators of angiogenesis under physiological and pathological disease states. Therefore, identification of microRNAs that may restore impaired angiogenesis in response to tissue injury may provide new targets for therapy. Using a microRNA microarray profiling approach, we identified a human-specific microRNA, miR-4674, that was significantly decreased in patients after myocardial tissue injury and had an endothelial cell (EC)-enriched expression pattern. Functionally, overexpression of miR-4674 markedly attenuated EC proliferation, migration, network tube formation, and spheroid sprouting, whereas blockade of miR-4674 had the opposite effects. Transcriptomic profiling, gene set enrichment analyses, bioinformatics, 3'-untranslated region (3'-UTR) reporter and microribonucleoprotein immunoprecipitation (miRNP-IP) assays, and small interfering RNA dependency studies revealed that miR-4674 regulates VEGF stimulated-p38 mitogen-activated protein kinase (MAPK) signaling and targets interleukin 1 receptor-associated kinase 1 (Irak1) and BICD cargo adaptor 2 (Bicd2) in ECs. Furthermore, Irak1 and Bicd2 were necessary for miR-4674-driven EC proliferation and migration. Finally, neutralization of miR-4674 increased angiogenesis, Irak1 and Bicd2 expression, and p38 phosphorylation in human skin organoids as a model of tissue injury. Collectively, targeting miR-4674 may provide a novel therapeutic target for tissue repair in pathological disease states associated with impaired angiogenesis.

MiR-26a-5p protects against myocardial ischemia/reperfusion injury by regulating the PTEN/PI3K/AKT signaling pathway.

Reperfusion strategies in acute myocardial infarction (AMI) can cause a series of additional clinical damage, defined as myocardial ischemia/reperfusion (I/R) injury, and thus there is a need for effective therapeutic methods to attenuate I/R injury. miR-26a-5p has been proven to be an essential regulator for biological processes in different cell types. Nevertheless, the role of miR-26a-5p in myocardial I/R injury has not yet been reported. We established an I/R injury model in vitro and in vivo. In vitro, we used cardiomyocytes to simulate I/R injury using hypoxia/reoxygenation (H/R) assay. In vivo, we used C57BL/6 mice to construct I/R injury model. The infarct area was examined by TTC staining. The level of miR-26a-5p and PTEN was determined by bioinformatics methods, qRT-PCR, and western blot. In addition, the viability and apoptosis of cardiomyocytes were separately detected by MTT and flow cytometry. The targeting relationship between miR-26a-5p and PTEN was analyzed by the TargetScan website and luciferase reporter assay. I/R and H/R treatment induced myocardial tissue injury and cardiomyocyte apoptosis, respectively. The results showed that miR-26a-5p was down-regulated in myocardial I/R injury. PTEN was found to be a direct target of miR-26a-5p. Furthermore, miR-26a-5p effectively improved viability and inhibited apoptosis in cardiomyocytes upon I/R injury by inhibiting PTEN expression to activate the PI3K/AKT signaling pathway. miR-26a-5p could protect cardiomyocytes against I/R injury by regulating the PTEN/PI3K/AKT pathway, which offers a potential approach for myocardial I/R injury treatment.

Protective effect of ulinastatin on myocardial injury after cardiopulmonary resuscitation in pigs

Objective To evaluate the protective effect of ulinastatin (UTI) on myocardial injury after post-cardiac arrest syndrome (PCAS) of cardiopulmonary resuscitation in pigs. Methods Twelve male 3-4 months pigs were randomly divided into two groups, UTI group and control group. The ventricular fibrillation (VF) animal model was replicated by programmed stimulation method. Among the 12 pigs, 11 pigs were successfully resuscitated by CPR after 5 min VF, of which, 6 pigs were in the UTI group and 5 pigs in the control group. Immediately after resuscitation, pigs in the UTI group was given 100 kU dissolved in 5 mL normal saline with slowly injection every 3 h until 24 h after recovery (no drug was given at 24 h). In the control group, 5 mL normal saline was given with same delivery time and frequency as that in the UTI group. The venous blood of the pigs was collected at VF, 2, 4, 6, 12, and 24 h after ROCS, and tumor necrosis factor -α (TNF-α), interleukin-6 (IL-6), superoxide dismutase (SOD), malondialdehyde (MDA), and ischemia modified albumin (IMA) were measured by enzyme-linked immunosorbent assay (ELISA) method. Because IMA was sensitive and increased rapidly, venous blood was detected at 1 h after ROSC, and the rest test time were same with the rest of the blood factors. Statistical analysis was performed using LSD-t test and variance analysis. The pigs were sacrificed 24 h after ROSC, and specimens from heart tissue were taken for HE staining. Results Before ventricular fibrillation in three groups, there was no significant difference in serum levels of inflammatory cytokines, oxidative stress indexes, and myocardial ischemia markers between the two groups (P>0.05). At 2 h after ventricular fibrillation, the levels of TNF-α and IL-6 level in the UTI group was significantly lower than those in the control group. At 4 h, MDA level in the UTI group was significantly lower than that in the control group (P 0.05). HE staining results showed that the damage degree of myocardial tissue in the UTI group was significantly lower than that in the control group at 24 h after ROSC. Conclusions UTI can significantly antagonize inflammatory response, reduce oxidative stress, and improve the myocardial tissue injury after resuscitation. It can protect myocardial injury after cardiopulmonary resuscitation. Key words: Ulinastatin; Cardiopulmonary resuscitation; Post-cardiac arrest syndrome; Tumor necrosis factor -αInterleukin-6; Superoxide dismutase; Ischemia modified albumin

Effect of lncRNA MALAT1 on rats with myocardial infarction through regulating ERK/MAPK signaling pathway.

To explore the effect of the long non-coding ribonucleic acid (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) on rats with myocardial infarction (MI) by regulating the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) signaling pathway. The Sprague- Dawley (SD) rat model of MI was established, and lncRNA MALAT1 was overexpressed using pcDNA-MALAT1 plasmids (MALAT1 group, n=10) and silenced using RNA interference technique (siMALAT1 group, n=10). The Sham group (n=10) was also set up. The transfection efficiency of lncRNA MALAT1 in rats was detected via Reverse Transcription-Polymerase Chain Reaction (RT-PCR). 2 weeks after the successful modeling, the cardiac function indexes were measured through magnetic resonance imaging (MRI) and echocardiography (ECG). The myocardial tissue injury was observed via hematoxylin-eosin (HE) staining, and the apoptosis of myocardial tissues was detected via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Moreover, the levels of the serum inflammatory factors were detected via enzyme-linked immunosorbent assay (ELISA), the messenger RNA (mRNA) expressions of Collagen I and III, the apoptosis, the and pathway genes were detected via RT-PCR. The expressions of ERK/MAPK pathway-related proteins in myocardial tissues were detected via Western blotting. The expression of lncRNA MALAT1 was remarkably increased in the MALAT1 group but evidently declined in the siMALAT1 group (p<0.05), indicating the successful transfection. The fractional shortening (FS, %) and ejection fraction (EF, %) were significantly restored in siMALAT1 group (p<0.05), suggesting that the silence of MALAT1 can improve the cardiac function after acute MI. The results of the HE staining and TUNEL assay manifested that siMALAT1 group had milder myocardial injury and decreased apoptosis compared with MALAT1 group. In the MALAT1 group, the mRNA expressions of Collagen I and III, Caspase3, ERK2, and MAPK were remarkably increased (p<0.05), while the mRNA expression of Bcl-2 was remarkably decreased (p<0.05). The above expressions had the opposite trends in siMALAT1 group. Besides, the protein expressions of ERK2 and MAPK in MALAT1 group were significantly increased (p<0.05). The downregulation of lncRNA MALAT1 can significantly improve the cardiac function after MI in SD rats mainly by inhibiting the ERK/MAPK pathway.

Spinosin and 6'''‑Feruloylspinosin protect the heart against acute myocardial ischemia and reperfusion in rats.

Investigating active compounds from Chinese herbal medicine that can rescue myocardial cells is a good approach to preserve cardiac function. Several herbal formulae that containing Semen Ziziphi Spinosae (SZS), also called Suanzaoren in Chinese, are clinically effective in the treatment of patients with acute myocardial infarction (AMI). The present study aimed to investigate the cardioprotective effects of spinosin and 6‴-feruloylspinosin, two flavonoid glycosides from SZS, in a rat model of myocardial ischemia and reperfusion. The left anterior descending artery (LAD) was occluded to induce myocardial ischemia. Spinosin or 6‴-feruloylspinosin (5 mg/kg) was intraperitoneally injected into rats 30 min before LAD ligation. The protein levels of myocardial enzymes in the serum, the extent of tissue injury and the rate of apoptosis were examined after AMI in rats with or without pretreatment with spinosin or 6‴-feruloylspinosin. Western blotting was performed to investigate the potential mechanisms underlying the function of these two flavonoid glycosides. The present results suggested that pretreatment with spinosin or 6‴-feruloylspinosin significantly attenuated myocardial tissue injury, and reduced myocardial enzyme release and cell apoptosis in AMI rats. In addition, spinosin treatment increased light chain 3B-II and 6‴-feruloylspinosin, and reduced p62, indicating that autophagy was promoted after drug treatments. Treatments of spinosin and 6‴-feruloylspinosin led to the reduction of glycogen synthase kinase-3β (GSK3β) phosphorylation at Tyr216, and the increase of peroxisome proliferator-activated receptor γ coactivator (PGC)-1α and its downstream signaling proteins, including nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and hemeoxygenase1 (HO-1). The present data suggested that SZS flavonoids could protect myocardial cells against acute heart ischemia-reperfusion, probably via the inhibition of GSK3β, which increased autophagy and the activity of the PGC-1α/Nrf2/HO-1 pathway.

Effects of miR-21 on hypertensive rats through PTEN/PI3K/Akt/mTOR signaling pathway.

The aim of this study was to investigate the effects of micro-ribonucleic acid (miR)-21 on hypertensive rats through the phosphatase and tensin homolog deleted on chromosome ten (PTEN)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. A total of 10 spontaneously hypertensive rats (SHRs) were selected as the model group. Meanwhile, 10 rats with the same age were enrolled in the normal control group. Real Time-fluorescence quantitative Polymerase Chain Reaction (qRT-PCR) was performed to detect the mRNA level of miR-21 in rats of the SHR model group and control group. The tail arterial diastolic pressure of rats in the awake and resting state was measured in both groups, respectively. Pathological sections were prepared to evaluate pathological changes in myocardial tissues. Subsequently, myocardial cells were isolated, cultured and transfected with miR-21 mimics and miR-21 inhibitor, respectively. Transfection efficiency was verified using fluorescence quantitative PCR. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay was utilized to determine the apoptosis level of myocardial cells. Furthermore, the expression levels of the signaling pathway-related proteins were detected via Western blotting assay. Fluorescence quantitative PCR results revealed that the expression level of miR-21 was significantly higher in the SHR model group (p<0.05). The diastolic pressure increased markedly in the SHR model group when compared with that in the control group (p<0.05). Subsequent hematoxylin and eosin (HE) staining indicated apparent myocardial tissue injury in the SHR model group (p<0.05). After transfection, the results showed that miR-21 inhibitor could effectively down-regulate the expression level of miR-21 in myocardial cells (p<0.05). Meanwhile, TUNEL staining revealed that the number of apoptotic cells in the miR-21 inhibitor group was remarkably higher than that of the other two groups (p<0.05). In addition, Western blotting results manifested that the protein expression levels of PTEN, PI3K, Akt and mTOR were significantly lower in the miR-21 mimics group (p<0.05), whereas was remarkably higher in the miR-21 inhibitor group (p<0.05). MiR-21 is involved in regulating the pathological symptoms and myocardial cell apoptosis in hypertensive rats through the PTEN/PI3K/Akt/mTOR signaling pathway.

Sumatriptan protects against myocardial ischaemia-reperfusion injury by inhibition of inflammation in rat model.

Ischemic heart disease is a leading cause of death on a global scale, placing major socio-economic burdens on health systems worldwide. Myocardial ischaemia and reperfusion (I/R)-induced tissue injury is associated with alteration in activity of inflammatory system and nitric oxide pathway. Sumatriptan, which is mainly used to relieve migraine headache, has recently been shown to exert anti-inflammatory properties. In this study, we aimed to assess the possible cardioprotective effect of sumatriptan in a rat model of I/R injury. Male Wistar rats were subjected to 30-min ligation of left anterior descending coronary artery and 120-min reperfusion. Animals were randomly divided into five groups: (1) Sham (2) I/R (3) I/R treated with sumatriptan (0.3 mg/kg i.p.) 20min after induction of I/R rats, (4) GR127935 (a selective antagonist of 5-HT1B/D serotonin receptors; 0.3mg/kg) 20min after induction of I/R, and (5) GR127935 (0.3mg/kg) 15min before administration of sumatriptan. Post-infarct treatment with sumatriptan increased left ventricular function, which was damaged in I/R animal's heart. Sumatriptan (0.3mg/kg) decreased lipid peroxidation, CK-MB and lactate dehydrogenase levels; tumor necrosis factor concentration; and Nf-ҡB' protein production. Treatment with sumatriptan significantly increased the endothelial nitric oxide synthase (eNOS) expression consequences nitric oxide metabolites' level in I/R rats. Also, injection of sumatriptan remarkably decreased myocardial tissue injury assessed by histopathological study. These findings suggest that sumatriptan may attenuate I/R injury via modulating the inflammatory responses and endothelial NOS activity. But therapeutic index of sumatriptan is narrow according to the result of this study.

Down-regulation of myocardial infarction associated transcript 1 improves myocardial ischemia-reperfusion injury in aged diabetic rats by inhibition of activation of NF-κB signaling pathway

ObjectiveThis study is performed to investigate the effect of long chain noncoding RNA myocardial infarction associated transcript 1 (MIRT1) on myocardial ischemia reperfusion (I/R) injury in aged diabetic rats. MethodsThe aged diabetic rat model and myocardial I/R injury model were established. Through injecting MIRT1 siRNA into caudal vein of rats, the cardiac function, myocardial pathological injury, myocardial fibrosis, cardiomyocytes apoptosis, oxidative stress and inflammatory injury of myocardial tissue of rats were measured. ResultsFor diabetic I/R rats, the expression of MIRT1 in myocardial tissue was increased, the activation of nuclear factor kappa B (NF-κB) signaling pathway was increased, the degree of damage to cardiac function was aggravated, the area of myocardial pathological injury and myocardial fibrosis was enlarged, the degree of cardiomyocytes apoptosis was increased, the degree of oxidative stress and inflammatory injury was increased. After inhibiting the expression of MIRT1, the activation of NF-κB signaling pathway was inhibited, the damage of cardiac function and cardiomyopathy was alleviated, the area of myocardial fibrosis was decreased, the degree of myocardial apoptosis was decreased, the degree of oxidative stress and inflammatory injury was obviously improved. ConclusionOur study highlights that down-regulation of MIRT1 improves myocardial I/R injury in aged diabetic rats by inhibition of activation of NF-κB signaling pathway.

Myocardial Partition Coefficient of Gadolinium: A Pilot Study in Patients With Acute Myocarditis, Chronic Myocardial Infarction, and in Healthy Volunteers

BackgroundThe tissue-blood partition coefficient (PC) of gadolinium, derived from T1 measurements, reflects myocardial connective tissue fraction and tissue injury, increasing in proportion with edema or fibrosis. We determined the myocardial PC of gadolinium in patients with acute myocarditis, chronic myocardial infarction (MI), and healthy volunteers. We hypothesized that the characteristics of the injured myocardium in patients with MI and myocarditis may differ and that the PC will be higher in chronically injured myocardium (MI) compared with acutely injured myocardium (myocarditis). MethodsWe performed late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) imaging and T1 mapping before and after administration of gadolinium (0.1 mmol/kg Gd-BOPTA) at 3 Tesla in 10 healthy volunteers (47.1 ± 12.4 years), 18 patients with chronic MI (62.5 ± 8.1 years), and 16 patients with acute myocarditis (42.5 ± 13.9 years). ResultsIn patients with chronic MI and focal scar by LGE, the whole left ventricular myocardial PC (0.45 ± 0.05) was higher compared with patients with MI without focal scar (0.39 ± 0.03, P = 0.02) but not significantly different from whole myocardial PC in volunteers (0.40 ± 0.05) or patients with myocarditis (0.41 ± 0.05). The PC in myocarditis scars was lower than in chronic MI scars (0.60 ± 0.12 vs 0.77 ± 0.16, P = 0.016). The relationships of PC and scar burden, expressed as % LGE, were similar and significant for the 2 groups (P = 0.042). ConclusionThe tissue-blood partition coefficient of Gd-BOPTA is elevated in areas of acute and chronic myocardial injury and may serve as a marker for disease activity and density of scars, which was found to be higher in chronic MI than in acute myocarditis.

Effects of a new compound containing Palmitoylethanolamide and Baicalein in myocardial ischaemia/reperfusion injury in vivo

BackgroundMyocardial ischemia/reperfusion (I/R) injury is the principal cause of death, happens after prolonged obstruction of the coronary arteries. The first intervention to limit myocardial damage is directed to restoration of perfusion, to avoid inflammatory response and a significant oxidative stress triggered by infarction. Palmitoylethanolamide (PEA), is a well-known fatty acid amide-signaling molecule that possess an important anti-inflammatory and analgesic effects. PEA does not hold the ability to inhibit free radicals formation. Baicalein, a bioactive component isolated from a Chinese herbal medicine, has multiple pharmacological activities, such as a strong anti-oxidative effects. PurposeA combination of PEA and Baicalein could have beneficial effects on oxidative stress produced by inflammatory response. Study designIn the present study we explored the effects of composite containing PEA and Baicalein in a model of myocardial I/R injury. MethodsMyocardial ischemia/reperfusion injury was induced by occlusion of the left anterior descending coronary artery for 30 min followed by 2 h of reperfusion. PEA-Baicalein (9:1), was administered (10 mg/kg) 5 min before the end of ischemia and 1 h after reperfusion. ResultsIn this study, we clearly demonstrated that PEA-Baicalein treatment decreases myocardial tissue injury, neutrophils infiltration, markers for mast cell activation expression as chymase and tryptase and pro-inflammatory cytokines production (TNF-α, IL-1β). Moreover, PEA-Baicalein treatment reduces stress oxidative and modulates Nf-kB and apoptosis pathways. ConclusionThese results support the idea that the association between PEA and Baicalein should be a potent candidate for the treatment of myocardial I/R injury.

Silencing of NOD2 protects against diabetic cardiomyopathy in a murine diabetes model.

The aim of the present study was to investigate the role of the nucleotide-binding oligomerization domain (NOD) 2 in high glucose (HG)-induced myocardial apoptosis and fibrosis in mice. Mouse models of diabetes were induced by streptozotocin (STZ). NOD2 expression was knocked down by injection of lentivirus-mediated short-hairpin RNA. Alternatively, small interfering RNA-NOD2 was transfected into cardiomyocytes and cardiac fibroblasts (CFs). A hemo-dynamic assay was used to assess the cardiac function in the mouse model. Hematoxylin and eosin, Masson and terminal deoxynucleotidyl transferase dUTP nick end labeling staining was performed to observe pathological changes and injury of myocardial tissue. The expression levels of NOD2, collagen I and III, and transforming growth factor-β (TGF-β) and apoptotic proteins were quantified by reverse transcription-quantitative polymerase chain reaction and western blotting. NOD2 silencing ameliorated diabetes-induced myocardial apoptosis and fibrosis in mice. NOD2, collagen I, collagen III, TGF-β and pro-apoptotic proteins were upregulated in the diabetic cardiomyopathy (DCM) model group, but interference of NOD2 suppressed these alterations in protein expression levels. NOD2 is upregulated in HG-induced primary cardiomyocytes and CFs. Suppression of NOD2 attenuated HG-induced cardiomyocyte apoptosis and proliferation of CFs. Overall, NOD2 silencing alleviated myocardial apoptosis and fibrosis in diabetic mice. The results of the present study demonstrated an understanding of the role of NOD2 in diabetes-induced cardiomyopathy, which provides a novel target and therapies for the prevention and treatment of DCM.

The Antioxidant Activity of Pistachios Reduces Cardiac Tissue Injury of Acute Ischemia/Reperfusion (I/R) in Diabetic Streptozotocin (STZ)-Induced Hyperglycaemic Rats.

Diabetes mellitus is an important risk factor for the development of heart pathology. Myocardial infarction is the cause of death occurring after prolonged ischemia of the coronary arteries. Restoration of blood flow is the first intervention against heart attack, although the process of restoring blood flow to the ischemic myocardium could cause additional injury. This phenomenon, termed myocardial ischemia-reperfusion (MI-R) injury, is characterized by the formation of oxygen radicals. Pistachios have significant glucose- and insulin-lowering effects and can improve the inflammatory contest by downregulating both the expression and the circulating levels of several metabolic risk markers. The monocyte/macrophage cell line J774 was used to assess the extent of protection by natural raw (NP) and roasted salted (RP) pistachios against lipopolysaccharide (LPS)-induced inflammation. Moreover, antioxidant activity of NP and RP was assessed in an in vivo model of paw edema in rats induced by carrageenan (CAR) injection in the paw. This study evaluates the antioxidant properties of pistachios on the inflammatory process associated with myocardial ischemia/reperfusion injury (I/R) in diabetic rats. Rats were pre-treated with either NP or RP pistachios (30 mg/kg) 18 h prior to the experimental procedure.Results: Here, we demonstrated that treatment with NP reduced myocardial tissue injury, neutrophil infiltration, adhesion molecules (ICAM-1, P-selectin) expression, proinflammatory cytokines (TNF-α, IL-1β) production, nitrotyrosine and PAR formation, NF-κB expression and apoptosis (Bax, Bcl-2) activation. This data clearly showes modulation of the inflammatory process, associated with MI-R injury, following administration of pistachios.

Protection by dimethyl fumarate against diabetic cardiomyopathy in type 1 diabetic mice likely via activation of nuclear factor erythroid-2 related factor 2

Oxidative stress and inflammation play key roles in the development of diabetic cardiomyopathy (DCM). Dimethyl fumarate (DMF), an FDA approved medicine for relapsing multiple sclerosis, has manifested its antioxidant and anti-inflammatory function mostly in the central nervous system. In this study, we investigated whether DMF could attenuate the development of DCM. Type 1 diabetes mouse model was established using multiple low-dose streptozotocin, and the diabetic mice were treated with DMF (10 mg/kg body weight) for 3 months. Cardiac functions were determined using echocardiography. Oxidative stress, pro-inflammatory cytokines and pro-fibrotic markers were determined with commercially available kits, real-time quantitative PCR or western blot techniques. DCM was characterized by diminished cardiac function, accompanied by oxidative stress and enhanced expression of pro-inflammatory cytokines. Diabetic cardiac tissue exhibited marked fibrosis, revealed by extracellular matrix deposition as determined by Sirius red staining of the myocardial tissues. Furthermore, Nrf2 and its downstream effectors were repressed in diabetic myocardium. On the contrary, diabetic animals treated with DMF exhibited blunted oxidative stress, inflammation, fibrosis and this correlated with Nrf2 activation. Our findings suggest that DMF could potentially thwart diabetes-induced myocardial tissue injury, likely via activation of Nrf2 function, providing firm impetus for future repurposing of DMF in the management of DCM.

Fisetin Confers Cardioprotection against Myocardial Ischemia Reperfusion Injury by Suppressing Mitochondrial Oxidative Stress and Mitochondrial Dysfunction and Inhibiting Glycogen Synthase Kinase 3β Activity.

Acute myocardial infarction (AMI) is the leading cause of morbidity and mortality worldwide. Timely reperfusion is considered an optimal treatment for AMI. Paradoxically, the procedure of reperfusion can itself cause myocardial tissue injury. Therefore, a strategy to minimize the reperfusion-induced myocardial tissue injury is vital for salvaging the healthy myocardium. Herein, we investigated the cardioprotective effects of fisetin, a natural flavonoid, against ischemia/reperfusion (I/R) injury (IRI) using a Langendorff isolated heart perfusion system. I/R produced significant myocardial tissue injury, which was characterized by elevated levels of lactate dehydrogenase and creatine kinase in the perfusate and decreased indices of hemodynamic parameters. Furthermore, I/R resulted in elevated oxidative stress, uncoupling of the mitochondrial electron transport chain, increased mitochondrial swelling, a decrease of the mitochondrial membrane potential, and induction of apoptosis. Moreover, IRI was associated with a loss of the mitochondrial structure and decreased mitochondrial biogenesis. However, when the animals were pretreated with fisetin, it significantly attenuated the I/R-induced myocardial tissue injury, blunted the oxidative stress, and restored the structure and function of mitochondria. Mechanistically, the fisetin effects were found to be mediated via inhibition of glycogen synthase kinase 3β (GSK3β), which was confirmed by a biochemical assay and molecular docking studies.

Implications of High-Sensitivity Cardiac Troponin I in Cardiology Clinical Practice

Background: High sensitivity troponin (hsTn) has better sensitivity for myocardial tissue injury detection compared to standard troponin assays, despite lower diagnostic specificity and lack of hsTn assay standardization. Objectives: To examine implications of introducing hsTnI in clinical practice. Methods: We retrospectively collected information of patients presented to a single tertiary cardiac referral centre with suspected acute coronary syndrome (ACS), who had ≥1 hsTnI sample (Abbott ARCHITECT STAT), from 1st June 2016-17th August 2016. Upper range limit (URL), i.e. 99th percentile, was defined as 34.2 ng/L, 15.6 ng/L and 26.2 ng/L for male, female and both gender (“overall”) respectively. Patients were divided into 4 groups - Group 1: hsTnURL but b3 times URL, Group 3: hsTn between 3-5 times URL and Group 4: hsTnN5 times URL. Results: Data from 366 patients was analysed: 227(62.0%), 34(9.3%), 13(3.6%), 92(25.1%) in Group 1, 2, 3 and 4 respectively. In Group 1 to 4, the proportion of ACS was 8.8%, 38.0%, 53.8%, 82.6% and proportion of MI were 0.8%, 29.4%, 53.8%. 82.6%. By using N5 times URL as cut-off, hsTnI has higher specificity and PPV, but lower sensitivity and NPV in diagnosis of ACS {(sensitivity:0.66, specificity:0.0.94, PPV0.83, NPV0.85), with ROC curve AUC:0.896, pb0.001, 95% CI:0.861-0.931}. Our analysis showed serial paired hsTn samples increase the PPV of hsTn to detect ACS. There was no significant difference between using hsTn URL “overall” or “gender-specific” for ACS diagnosis. Kaplan-Meier analysis showed 30-day all-cause mortality in the group with maximal hsTn value NURL is significant higher (pb0.001). Multiple-logistic regression showed that URL of hsTn was an independent variable for 30-day all-cause mortality (p<0.001). Conclusions: Introducing hsTnI has led to the recognition of a large proportion of patients with minor cardiac troponin increases (above URL of 99th percentile but b5 times URL), the majority of whom do not have ACS or MI. There is no significant difference in using “overall” and “gender-specific” URL in diagnosing ACS. Using 5 times above URL and serial hsTn will increase PPV to detect ACS. Maximal HsTn value N99th percentile is independently associated with 30-day all-cause mortality.