Cardioprotective Effects In Rats Research Articles

Liraglutide Attenuates Diabetic Cardiomyopathy via the ILK/PI3K/AKT/PTEN Signaling Pathway in Rats with Streptozotocin-Induced Type 2 Diabetes Mellitus.

One of the possible candidates for the treatment of diabetic cardiomyopathy is liraglutide, a glucagon-like peptide-1 receptor (GLP1R) agonist. In this study, the impacts of liraglutide on the integrin-linked kinase (ILK)-related PI3K/AKT axis in rats with type 2 diabetes induced via streptozotocin were examined. Twenty-four Wistar albino rats were distributed in four different groups, and a high-fat diet and streptozotocin were used to induce type 2 in two groups. Rats in the untreated control groups were administered 0.9% NaCl solution over a 6-week period, and those in the treatment groups were administered 0.9% NaCl for 3 weeks, followed by subcutaneous injection of liraglutide (150 μg/kg) for an additional 3 weeks. In the liraglutide-treated diabetic group, the heart-to-body weight ratio was significantly reduced, levels of cardiac biomarkers, troponin I and creatine-kinase-MB, were improved; activities of antioxidant enzymes, glutathione peroxidase and superoxide dismutase, were increased; and levels of malondialdehyde were decreased. Western blotting and immunohistochemical studies revealed increased levels of ILK, P-PI3K, P-AKT, and BCL2, as well as those of caspase 3, BAX, and P-PTEN, indicating mitigation of cardiomyocyte apoptosis. Our results show that liraglutide, by targeting GLP1Rs, enhances the expression of proteins in the ILK/PI3K/AKT/PTEN pathway and thereby exerts its cardioprotective effects in rats with DCM.

A novel micropeptide, Slitharin, exerts cardioprotective effects in myocardial infarction.

Micropeptides are an emerging class of proteins that play critical roles in cell signaling. Here, we describe the discovery of a novel micropeptide, dubbed slitharin (Slt), in conditioned media from Cardiosphere-derived cells (CDCs), a therapeutic cardiac stromal cell type. We performed mass spectrometry of peptide-enriched fractions from the conditioned media of CDCs and a therapeutically inert cell type (human dermal fibrobasts). We then evaluated the therapeutic capacity of the candidate peptide using an in vitro model of cardiomyocyte injury and a rat model of myocardial infarction. We identified a novel 24-amino acid micropeptide (dubbed Slitharin [Slt]) with a non-canonical leucine start codon, arising from long intergenic non-coding (LINC) RNA 2099. Neonatal rat ventricular myocytes (NRVMs) exposed to Slt were protected from hypoxic injury in vitro compared to a vehicle or scrambled control. Transcriptomic analysis of cardiomyocytes exposed to Slt reveals cytoprotective capacity, putatively through regulation of stress-induced MAPK-ERK. Slt also exerted cardioprotective effects in rats with myocardial infarction as shown by reduced infarct size 48 h post-injury. Conclusions and clinical relavance: Thus, Slt is a non-coding RNA-derived micropeptide, identified in the extracellular space, with a potential cardioprotective function.

Remote ischemic preconditioning-induced late cardioprotection: possible role of melatonin-mitoKATP-H2S signaling pathway.

Remote ischemic preconditioning (RIPC) confers cardioprotection against ischemia reperfusion (IR) injury. However, the precise mechanisms involved in RIPC-induced cardioprotection are not fully explored. The present study was aimed to identify the role of melatonin in RIPC-induced late cardioprotective effects in rats and to explore the role of H2S, TNF-α and mitoKATP in melatonin-mediated effects in RIPC. Wistar rats were subjected to RIPC in which hind limb was subjected to four alternate cycles of ischemia and reperfusion of 5 min duration by using a neonatal blood pressure cuff. After 24 h of RIPC or ramelteon-induced pharmacological preconditioning, hearts were isolated and subjected to IR injury on the Langendorff apparatus. RIPC and ramelteon preconditioning protected the hearts from IR injury and it was assessed by a decrease in LDH-1, cTnT and increase in left ventricular developed pressure (LVDP). RIPC increased the melatonin levels (in plasma), H2S (in heart) and decreased TNF-α levels. The effects of RIPC were abolished in the presence of melatonin receptor blocker (luzindole), ganglionic blocker (hexamethonium) and mitochondrial KATP blocker (5-hydroxydecanoic acid). RIPC produce delayed cardioprotection against IR injury through the activation of neuronal pathway, which may increase the plasma melatonin levels to activate the cardioprotective signaling pathway involving the opening of mitochondrial KATP channels, decrease in TNF-α production and increase in H2S levels. Ramelteon-induced pharmacological preconditioning may also activate the cardioprotective signaling pathway involving the opening of mitochondrial KATP channels, decrease in TNF-α production and increase in H2S levels.

Danshensu exerts cardioprotective effects in rats with acute myocardial infarction via reduction of infiltration of inflammatory cells and mitigation of myocardial fibrosis

Purpose: To investigate the mitigative impact of danshensu on heart tissues in acute myocardial infarction (AMI) rats, and the mechanism of action involved.
 Methods: Seventy-five male Sprague-Dawley (SD) rats were used in this study. After successful induction of myocardial infarction, the rats were divided into model group (MG), low-dose danshensu group (LDG; 15 mg/kg), middle-dose danshensu group (MDG; 30 mg/kg), and high-dose danshensu group (HDG; 60 mg/kg), with 15 rats per group. Rats in sham group (SG; n = 15) served as control. Serum levels of biochemical indicators and expressions of various proteins in myocardial tissue were determined using Western blotting, and compared amongst the rat groups.
 Results: Serum cTnI concentrations in MDG and HDG were significantly decreased, relative to the corresponding concentrations in MDG. There were significantly lower serum concentrations of IL-1 in MDG and HDG than in model rats. Rats in HDG had lower serum IL-6 concentration than MG rats, while TNF-α levels were down-regulated in MDG and HDG, relative to MG (p < 0.05).
 Conclusion: Danshensu protects the heart function of rats with AMI by decreasing inflammationderived cells and mitigating myocardial fibrosis. Thus, it may be useful in the management of AMI in humans but clinical trials are necessary to ascertain this.
 Keywords: Danshens; Acute myocardial infarction; Myocardial ischemia-reperfusion; Myocardial fibrosis

Tetramisole is a new IK1 channel agonist and exerts IK1 -dependent cardioprotective effects in rats.

Cardiac ischemia, hypoxia, arrhythmias, and heart failure share the common electrophysiological changes featured by the elevation of intracellular Ca2+ (Ca2+ overload) and inhibition of the inward rectifier potassium (IK1) channel. IK1 channel agonists have been considered a new type of anti‐arrhythmia and cardioprotective agents. We predicted using a drug repurposing strategy that tetramisole (Tet), a known anthelminthic agent, was a new IK1 channel agonist. The present study aimed to experimentally identify the above prediction and further demonstrate that Tet has cardioprotective effects. Results of the whole‐cell patch clamp technique showed that Tet at 1–100 μmol/L enhanced IK1 current, hyperpolarized resting potential (RP), and shortened action potential duration (APD) in isolated rat cardiomyocytes, while without effects on other ion channels or transporters. In adult Sprague–Dawley (SD) rats in vivo, Tet showed anti‐arrhythmia and anticardiac remodeling effects, respectively, in the coronary ligation‐induced myocardial infarction model and isoproterenol (Iso, i.p., 3 mg/kg/day, 10 days) infusion‐induced cardiac remodeling model. Tet also showed anticardiomyocyte remodeling effect in Iso (1 μmol/L) infused adult rat ventricular myocytes or cultured H9c2 (2‐1) cardiomyocytes. Tet at 0.54 mg/kg in vivo or 30 μmol/L in vitro showed promising protections on acute ischemic arrhythmias, myocardial hypertrophy, and fibrosis. Molecular docking was performed and identified the selective binding of Tet with Kir2.1. The cardioprotection of Tet was associated with the facilitation of IK1 channel forward trafficking, deactivation of PKA signaling, and inhibition of intracellular calcium overload. Enhancing IK1 may play dual roles in anti‐arrhythmia and antiventricular remodeling mediated by restoration of Ca2+ homeostasis.

Dose-dependent effects of perfluorocarbon-based blood substitute on cardiac function in myocardial ischemia-reperfusion injury.

The main goal of this study was to investigate the cardioprotective properties in terms of effects on cardiodynamics of perfluorocarbon emulsion (PFE) in ex vivo-induced ischemia-reperfusion injury of an isolated rat heart. The first part of the study aimed to determine the dose of 10% perfluoroemulsion (PFE) that would show the best cardioprotective effect in rats on ex vivo-induced ischemia-reperfusion injury of an isolated rat heart. Depending on whether the animals received saline or PFE, the animals were divided into a control or experimental group. They were also grouped depending on the applied dose (8, 12, 16ml/kg body weight) of saline or PFE. We observed the huge changes in almost all parameters in the PFE groups in comparison with IR group without any pre-treatment. Calculated in percent, dp/dt max was the most changed parameter in group treated with 8mg/kg, while the dp/dt min, SLVP, DLVP, HR, and CF were the most changed in group treated with 16mg/kg 10h before ischemia. The effects of 10% PFE are more pronounced if there is a longer period of time from application to ischemia, i.e., immediate application of PFE before ischemia (1h) gave the weakest effects on the change of cardiodynamics of isolated rat heart. Therefore, the future of PFE use is in new indications and application methods, and PFE can also be referred to as antihypoxic and antiischemic blood substitute with mild membranotropic effects.

Inhibition of Rhoa/Rho Kinase by Ibuprofen Exerts Cardioprotective Effect against Ischemic Reperfusion Injury in Rats

Ischemic Reperfusion Injury is the main cause of mortality globally, researchers are concentrating their efforts on heart protection. Ibuprofen inhibits rho-kinase, a downstream effector of a protein implicated in Ischemic Reperfusion Injury. The goal of this study is to deter Ischemic Reperfusion Injuryne whether ibuprofen has a cardioprotective effect in rats. In an experimental animal, Ischemic Reperfusion Injury was produced by undergoing coronary artery ligation operations. The rats were rando Ischemic Reperfusion Injuryzed into six groups: (I) Normal; (II) model; (III) Sham; (IV-VI) ISO þ ibuprofen (30, 60 and 90 mg/kg p.o). At the end of surgery Langendorff, cardiac marker enzymes, electrolytes, anti-oxidants and gene expression of ROCK-1 were investigated. Pre-treatment with ibuprofen (30, 60, 90 mg/kg, p.o.) for 21 days normalise Blood pressure and improved the ECG pattern, left ventricular function by avoiding ROCK-mediated damage, and prevented the rise in CK-MB, LDH, and Troponin-I and electrolyte level by maintaining cellular integrity. Further, ibuprofen downregulate the mRAN expression of ROCK-1 and preserved the cellular architecture of myocardial tissue. Ibuprofen provided cardioprotection in a model of myocardial infarction, by restoring most of the altered physical, physiological, bioche Ischemic Reperfusion Injurycal, haemodyna Ischemic Reperfusion Injuryc parameters, antioxidant status, and histological changes and by inhibiting ROCK-1 mRNA expression.

Comparative evaluation of metformin and liraglutide cardioprotective effect in rats with impaired glucose tolerance

Impaired glucose tolerance (IGT) increases cardiovascular risk and can enlarge myocardial infarction (MI) incidence and severity. There is lack of information about cardioprotective potential of glucose-lowering drugs in IGT. We aimed to evaluate the sustainability of myocardium to ischemia–reperfusion injury in diabetic and IGT rats and to study cardioprotective action of metformin and liraglutide. Type 2 diabetes mellitus (DM) and IGT were modelled in Wistar rats by high-fat diet and streptozotocin + nicotinamide. 4 weeks after rats were divided into 4 groups: DM (without treatment) (n = 4), IGT (without treatment) (n = 4), IGT + MET (metformin 200 mg/kg per os once daily 8 weeks) (n = 4), IGT + LIRA (liraglutide 0.06 mg/kg s.c. once daily for 8 weeks) (n = 4). Control (n = 6) and high-fat diet (n = 8) groups were made for comparison. After 8 weeks ischemia–reperfusion injury in isolated hearts was performed. Hemodynamic parameters were evaluated and MI size was measured by staining of myocardium slices in triphenyltetrazolium chloride solution. Blood glucose level was measured during the study. Both IGT and DM led to similar worsening of hemodynamic parameters during ischemia–reperfusion period, in comparison with control group. MI size in IGT (56.76 (51.58; 69.07) %) and DM (57.26 (45.51; 70.08) %) groups was significantly larger than that in control group (42.98 (33.26; 61.84) %) and did not differ between each other. MI size in high-fat diet group (56.98 (47.11; 62.83) %) was as large as in IGT and DM groups (p > 0.05). MI size in IGT + MET (42.11 (38.08; 71.96) %) and IGT + LIRA (42.50 (31.37; 60.40) %) was smaller than in both DM and IGT groups (p < 0.05 for multiple comparison). Myocardium damage size did not differ in IGT + MET and IGT + LIRA groups (p > 0.05). Only LIRA, but not MET administration to IGT rats led to ischemic contracture reduction. Glycemic control was similarly satisfactory in IGT, IGT + MET, IGT + LIRA groups. Thus, IGT and DM have similarly pronounced negative influence on hemodynamics and MI size in rat transient global ischemia ex vivo. Obesity development also has negative impact on the MI size. Both MET and LIRA have infarct-limiting effect independent on their influence on glucose level. LIRA, but not MET, diminishes ischemic contracture in IGT rats.

Acetylcholinesterase inhibitor protects against cardiac ischaemia/reperfusion injury via enhancing mitophagy and rebalancing mitochondrial dynamics

Abstract Background Ischaemic heart disease is the most common cause of death globally. Although reperfusion therapy is essential to restore myocardial blood flow, it can also damage heart tissues, this process is known as ischaemia/reperfusion (I/R) injury. Cardiac autonomic imbalance including sympathetic overactivity and diminished parasympathetic activity plays an important role in cardiac I/R injury, resulting in left ventricular (LV) dysfunction. Increased vagus nerve activity by an electrical stimulation from an implantable medical device has been shown to be cardioprotective in cardiac I/R injury. However, the role of pharmacological intervention that increases parasympathetic activity on the heart during I/R is not clear. Purpose We investigated the effects of a parasympathomimetic drug, donepezil, on the heart with I/R injury. We hypothesized that donepezil exerts cardioprotective effects in rats with cardiac I/R injury by attenuating the impairment of cardiac mitochondrial function, mitochondrial dynamics and mitophagy, resulting in improved LV function. Methods Forty male Wistar rats were randomly divided into sham and I/R groups. In I/R group, rats were subjected to acute cardiac I/R injury by ligating left anterior descending coronary artery (LAD) for 30 mins followed by reperfusion for 120 mins, while sham group had similar operation but did not have LAD ligation. Moreover, rats in the I/R group were randomly assigned to be treated with either saline (vehicle group) or donepezil 3 mg/kg by intravenous injection. In donepezil-treated rats, they were divided into 3 subgroups to receive the drug at one of the following time-points; before ischaemia, or during ischaemia, or at the onset of reperfusion. During I/R protocol, LV function was recorded. At the end of protocol, the heart was removed to determine infarct size, cardiac mitochondrial function, mitochondrial dynamics, and mitophagy. Results Rats with cardiac I/R injury showed increased infarct size when compared to sham group (Fig. 1A). Rats in all donepezil-treated groups showed reduction of infarct size compared to the vehicle group. This accounts for ∼63%, ∼47%, and ∼44% reduction for the treatment before ischaemia, during ischaemia and onset of reperfusion, respectively. In addition, all donepezil-treated rats had improved LV function by attenuating the reduction of LV ejection fraction (Fig. 1B). The reduction in cardiac mitochondrial ROS production (Fig. 1C), increased mitophagy as indicated by increased PINK-1 expression (Fig. 1D), and rebalancing mitochondrial dynamics were also found in all donepezil-treated rats. Conclusion Donepezil protects against cardiac I/R injury by reducing mitochondrial ROS production, enhancing mitophagy, and improving mitochondrial dynamics, leading to decreased infarct size and improved cardiac function. Figure 1. The effects of donepezil in cardiac I/R Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Thailand Research Fund grants TRF-Royal Golden Jubilee Program (TK and NC), RTA6180003 (SCC), RSA6180056 (SP); The NSTDA Research Chair grant from the National Science and Technology Development Agency Thailand (NC)

Acute dapagliflozin administration exerts cardioprotective effects in rats with cardiac ischemia/reperfusion injury

BackgroundA sodium-glucose co-transporter 2 (SGLT-2) inhibitor had favorable impact on the attenuation of hyperglycemia together with the severity of heart failure. However, the effects of acute dapagliflozin administration at the time of cardiac ischemia/reperfusion (I/R) injury are not established.MethodsThe effects of dapagliflozin on cardiac function were investigated by treating cardiac I/R injury at different time points. Cardiac I/R was instigated in forty-eight Wistar rats. These rats were then split into 4 interventional groups: control, dapagliflozin (SGLT2 inhibitor, 1 mg/kg) given pre-ischemia, at the time of ischemia and at the beginning of reperfusion. Left ventricular (LV) function and arrhythmia score were evaluated. The hearts were used to evaluate size of myocardial infarction, cardiomyocyte apoptosis, cardiac mitochondrial dynamics and function.ResultsDapagliflozin given pre-ischemia conferred the maximum level of cardioprotection quantified through the decrease in arrhythmia, attenuated infarct size, decreased cardiac apoptosis and improved cardiac mitochondrial function, biogenesis and dynamics, leading to LV function improvement during cardiac I/R injury. Dapagliflozin given during ischemia also showed cardioprotection, but at a lower level of efficacy.ConclusionsAcute dapagliflozin administration during cardiac I/R injury exerted cardioprotective effects by attenuating cardiac infarct size, increasing LV function and reducing arrhythmias. These benefits indicate its potential clinical usefulness.

Antihypertensive effects of the hydro-ethanol extract of Senecio serratuloides DC in rats

BackgroundSenecio serratuloides DC is used in folk medicine for treating hypertension, skin disorders, internal and external sores, rashes, burns and wounds. This study aimed at investigating the antihypertensive effects of the hydroethanol extract of S. serratuloides (HESS) in N-Nitro-L-arginine methyl ester (L-NAME) induced hypertension in rats.Methods: Acute toxicity of HESS was first determined to provide guidance on doses to be used in this study. Lorke’s method was used to determine safety of the extract in mice. Female Wistar rats were treated orally once daily with L-NAME (40 mg/kg) for 4 weeks and then concomitantly with L-NAME (20 mg/kg) and plant extract (150 and 300 mg/kg), captopril (20 mg/kg) or saline as per assigned group for 2 weeks followed by a 2-week period of assigned treatments only. Blood pressure was monitored weekly. Lipid profile, nitric oxide, renin and angiotensin II concentrations were determined in serum while mineralocorticoid receptor concentration was quantified in the kidney homogenate. Nitric oxide (NO) concentration was determined in serum and cardiac histology performed.ResultsHESS was found to be non-toxic, having a LD50 greater than 5000 mg/kg. Blood pressure increased progressively in all animals from the second week of L-NAME treatment. HESS treatment significantly and dose-dependently lowered systolic blood pressure (p < 0.001), diastolic blood pressure (p < 0.01), low density lipoprotein cholesterol (p < 0.01) and triglycerides (p < 0.01). It significantly prevented L-NAME induced decrease in serum angiotensin II (p < 0.01), high density lipoprotein cholesterol (p < 0.001) and serum nitric oxide concentrations (p < 0.001). HESS also significantly (p < 0.01) prevented collagen deposition in cardiac tissue.ConclusionThe hydro-ethanol extract of Senecio serratuloides showed antihypertensive, antihyperlipidemic and cardioprotective effects in rats thus confirming its usefulness in traditional antihypertensive therapy and potential for antihypertensive drug development.

PL - 027 Up-regulation of NRG1 improves cardiac repair in zebra fish and involved in the cardioprotective effects of exercise training in rats of myocardial infarction

Objective Myocardial infarction (MI) remains a leading cause of morbidity and mortality worldwide. Exercise training could improve cardiac function following MI. However, the mechanisms are still not well-known. Neuregulin 1 (NRG1)plays an important role in heart development and regeneration.In this study, we investigated the effect of NRG1 on cardiac regeneration in a zebrafish model, detected whether exercise could improve cardiac function through regulating NRG1 expression in infarcted heart and explore the possible role of up-regulation of NRG1 in skeletal muscle play in the cardioprotective effects in rats with MI.&#x0D; Methods Transgenic zebrafish line, cmlc2:CreERandβ-act2:BSNrg1,wereusedto study the effect of NRG1 on heart growth and regeneration after injury. PCNA was detected by immunofluorescence staining andmRNAexpression of gata4, nkx2.5, tbx5, smyd1b, hsp90α and murf were tested by RT-PCR.Sprague-Dawley rats were used to establish MI model and underwent fourweeks of exercise training (ET) or pAAV-{dMCK promoter}rNRG1-eGFP intervention.AG1478 was used asan inhibitor of NRG1/ErbBs signaling pathway. Cardiac function and structure,cardiomyocyte proliferation and NRG1 expression were detected in the heart or skeletal.&#x0D; Results Cardiac-specific overexpression of NRG1 induced cardiac hypertrophy and cardiomyocyte proliferation, regulated the mRNA expression of gata4, nkx2.5, tbx5, smyd1b, hsp90α andmurf in uninjuriedzebrafish, and promote cardiac repair and regeneration after injury in the zebrafish.Exercise activated NRG1/ErbBs signaling pathway, improved cardiac remodeling and heart function, enhanced cardiomyocyte proliferation, reduced cardiomyocyte apoptosis, ROS level and MuRF1 protein expression in rats with MI. BlockingErbB signaling attenuated the ET-induced cardioprotection effects in rat with MI.up-regulation of NRG1 expression in skeletal muscle could increase the protein level of NRG1 in serum and infarcted heart, improve cardiomyocyte proliferation and reduce the level of cardiac fibrosis, finally promote cardiac function.&#x0D; Conclusions Up-regulation of NRG1 expression in the heart or skeletal musclemay be one of the underlying mechanisms of thebeneficial effects of exercise training following MI.

Cardiovascular Activities of an Ayurvedic Preparation Amalaki Rasayan in Rat Model

The importance of traditional or alternative medicines including Ayurvedic drugs are increasing day by day because of their necessary pharmacological actions and fewer side effects. Previous investigators showed hypolipidemic and cardioprotective effects of Amla which is the active ingredient of Amalaki Rasayan. It is an ayurvedic formulation that contains extracts of Phyllanthus emblica plant. Therefore, this study has been conducted to investigate the scientific evidence of its cardioprotective effects in rats by recording electrocardiographic tracings. Rats, of either sex, were treated with preparation containing extracts of Phyllanthus emblica in doses 800 μg/kg bodyweight, 1600 μg/kg body weight and 3200 μg/kg body weight through intraperitoneal route. Electrocardiogram along with heart rate and other parameters were measuredin rat model before and after administration of Amalaki Rasayan. It was evident that Amalaki Rasayan, at a dose of 800 μg/kg, was safe but 1600 μg/kg and 3200 μg/kg produced abnormal activities in the heart. It can be inferred from the study that, the ayurvedic preparation Amalaki Rasayan possesses significant cardioprotective effectBangladesh Pharmaceutical Journal 20(2): 157-164, 2017

Cardioprotective Effects of Morroniside in Rats Following Acute Myocardial Infarction.

The aim of this study is to investigate the cardioprotective effects of morroniside in rats following acute myocardial infarction. An acute myocardial infarction (AMI) was induced by ligating the anterior descending coronary artery (LAD) [1]. Following AMI, morroniside was administered intragastrically for 24h at doses of 45, 90, and 180mg/kg, respectively. Biomarkers such as creatine kinase (CK-MB), lactate dehydrogenase (LDH), ɑ-hydroxybutyrate dehydrogenase (ɑ-HBDH), and aspartate aminotransferase (AST) activities in AMI rats in the serum were detected with commercial kits [2]. Following AMI, morroniside was administered intragastrically for 72h at doses of 45, 90, and 180mg/kg/d, respectively. The expression of nuclear factor kappa B (NF-κB) in cardiac myocardium was detected by western blotting analysis. Meanwhile, cardiac function was measured by echocardiography. We observed morroniside decreased the levels of CK-MB, LDH, ɑ-HBDH, and AST activities in AMI rats after 24h. We also found that morroniside reduced the expression of NF-κB in cardiac myocardium at 72h post AMI rats. Further, cardiac function was improved by administration of morroniside. Collectively, our findings demonstrated that morroniside had cardioprotective effects in rats following acute myocardial infarction. Attenuation of inflammation might contribute to the cardioprotective effects of morroniside.

Salidroside suppressing LPS-induced myocardial injury by inhibiting ROS-mediated PI3K/Akt/mTOR pathway in vitro and in vivo.

The purpose of the present study was to investigate the effect of salidroside (Sal) on myocardial injury in lipopolysaccharide (LPS)‐induced endotoxemic in vitro and in vivo. SD rats were randomly divided into five groups: control group, LPS group (15 mg/kg), LPS plus dexamethasone (2 mg/kg), LPS plus Sal groups with different Sal doses (20, 40 mg/kg). Hemodynamic measurement and haematoxylin and eosin staining were performed. Serum levels of creatine kinase (CK), lactate dehydrogenase, the activities of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH‐px), glutathione, tumour necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), and interleukin‐1β (IL‐1β) were measured after the rats were killed. iNOS, COX‐2, NF‐κB and PI3K/Akt/mTOR pathway proteins were detected by Western blot. In vitro, we evaluated the protective effect of Sal on rat embryonic heart‐derived myogenic cell line H9c2 induced by LPS. Reactive oxygen species (ROS) in H9c2 cells was measured by flow cytometry, and the activities of the antioxidant enzymes CAT, SOD, GSH‐px, glutathione‐S‐transferase, TNF‐α, IL‐6 and IL‐1β in cellular supernatant were measured. PI3K/Akt/mTOR signalling was examined by Western blot. As a result, Sal significantly attenuated the above indices. In addition, Sal exerts pronounced cardioprotective effect in rats subjected to LPS possibly through inhibiting the iNOS, COX‐2, NF‐κB and PI3K/Akt/mTOR pathway in vivo. Furthermore, the pharmacological effect of Sal associated with the ROS‐mediated PI3K/Akt/mTOR pathway was proved by the use of ROS scavenger, N‐acetyl‐l‐cysteine, in LPS‐stimulated H9C2 cells. Our results indicated that Sal could be a potential therapeutic agent for the treatment of cardiovascular disease.

Cardioprotective Effects of the Ethanol Leaf Extract of Andrographis Paniculata in Isoproterenol‐induced Myocardial Infarction in Rats

Andrographis paniculata commonly known as king of bitters is an annual ‐ branched, erect ‐ running 1/2 to 1 meter in height. The aerial parts of the plant (leaves and stems) are used to extract the active phytochemicals. It grows abundantly in south eastern Asia: India (and Sri Lanka), Pakistan and Indonesia ‐ but it is cultivated extensively in China and Thailand, the East and West Indies, and Mauritius. Modern pharmacological studies have demonstrated its hepatoprotective, antithrombotic, anti‐inflammatory, immunostimulant, antimalarial, antihyperglycemic and cardioprotective properties. Because of its well‐known medicinal properties, this study was designed to evaluate the cardioprotective effect of the Nigerian species of Andrographis paniculata (AP) ethanol leaf extracts in isoproterenol‐induced myocardial infarction in rats using electrocardiogram, blood pressure changes as well as anti‐oxidant status.Male rats were randomly divided into 7 groups of 7 animals per group. While group A served as control, group B was administered with Isoproterenol (ISO), group C was administered with Enalapril (10 mg/kg), but groups D, E and F were pretreated respectively with EEAP in three different doses (100, 200 and 400 mg/kg) orally for 7 days and group G was administered with 200 mg/kg EEAP post treatment with ISO. Myocardial infarction was induced intraperitoneally (i.p.) using isoproterenol (85 mg/kg) at interval of 24 h on 8th &amp; 9th day in pretreated groups while on 1st &amp; 2nd day in post treated group. The electrocardiogram, heart rate and blood pressure measurements were carried out on the 10th day in all groups and all animals were sacrificed afterwards and heart tissues were collected, homogenized, and centrifuged for anti‐oxidant studies.ISO injection (85 mg/kg i.p.) produced changes in ECG pattern including prolonged QT interval and notches. ISO injection also produced a significant decrease in SAP, DAP and MAP levels. Although the extract did not amend the changes in ECG to normal but significantly increased the hemodynamics parameters. The extract increased antioxidant enzymes (SOD, GPX, GST, and GSH) and reduced oxidative stress markers (MDA using lipid peroxidation, H2O2, PT and NPT).It could be concluded that the ethanol leaf extract of Andrographis paniculata exhibited cardioprotective effect in rats showing potent anti‐oxidant properties as well as improving the haemodynamic changes in the rats. This cardioprotective effect was similar to that of enalapril, an ACE inhibitor used in this study.Support or Funding InformationNational Research Foundation of the Tertiary Research Fund, Nigeria.

Echinodorus grandiflorus: Ethnobotanical, phytochemical and pharmacological overview of a medicinal plant used in Brazil

Echinodorus grandiflorus (Cham. & Schltdl.) Micheli is a native Brazilian species used in traditional practices for the treatment of several conditions such as inflammatory diseases, arthritis and hypertension. Through a systematic review of the accumulated knowledge about the species E. grandiflorus, the botanical, phytochemistry, ethnobotanical and pharmacological properties of this medicinal plant demonstrates its potential to naturally provide anti-inflammatory and anti-oxidant with a special emphasis on anti-hypertensive and cardioprotective effects. The body of literature reports that the chemical composition of crude E. grandiflorus extracts are notably composed of diterpenoids and flavonoids metabolites. Pharmacological studies have shown that oral treatments using the hydroalcoholic extracts of leaves from this plant has a significant anti-inflammatory, anti-hypertensive, diuretic and cardioprotective effects in rats with no toxicity. The holistic activities of complex extracts are corroborated by the individuals mechanisms of action, as well as, synergistic benefits attributed to the isolated chemical major constituents in this species. In light of the serious health concerns ascribed, it is important to investigate medicinal plant species with histories of traditional use for circulatory problems to meet the growing demands by scientifically validating their use and safety.

Cardiotonic Pill Reduces Myocardial Ischemia-Reperfusion Injury via Increasing EET Concentrations in Rats.

Accumulating data suggest that epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid, both cytochrome P450 (P450) enzyme metabolites of arachidonic acid (AA), play important roles in cardiovascular diseases. For many years, the cardiotonic pill (CP), an herbal preparation derived from Salviae Miltiorrhizae Radix et Rhizoma, Notoginseng Radix et Rhizoma, and Borneolum Syntheticum, has been widely used in China for the treatment of coronary artery disease. However, its pharmacological mechanism has not been well elucidated. The purpose of this study was to investigate the chronic effects of the CP on myocardial ischemia-reperfusion injury (MIRI) and AA P450 enzyme metabolism in rats (in vivo) and H9c2 cells (in vitro). The results showed that CP dose dependently (10, 20, and 40 mg/kg/d; 7 days) mitigated MIRI in rats. The plasma concentrations of EETs in CP-treated ischemia-reperfusion (I/R) rats (40 mg/kg/d; 7 days) were significantly higher (P < 0.05) than those in controls. Cardiac Cyp1b1, Cyp2b1, Cyp2e1, Cyp2j3, and Cyp4f6 were significantly induced (P < 0.05); CYP2J and CYP2C11 proteins were upregulated (P < 0.05); and AA-epoxygenases activity was significantly increased (P < 0.05) after CP (40 mg/kg/d; 7 days) administration in rats. In H9c2 cells, the CP also increased (P < 0.05) the EET concentrations and showed protection in hypoxia-reoxygenation (H/R) cells. However, an antagonist of EETs, 14,15-epoxyeicosa-5(Z)-enoic acid, displayed a dose-dependent depression of the CP's protective effects in H/R cells. In conclusion, upregulation of cardiac epoxygenases after multiple doses of the CP-leading to elevated concentrations of cardioprotective EETs after myocardial I/R-may be the underlying mechanism, at least in part, for the CP's cardioprotective effect in rats.

Mechanism of QSYQ on anti-apoptosis mediated by different subtypes of cyclooxygenase in AMI induced heart failure rats.

BackgroundQi-shen-yi-qi (QSYQ), one of the most well-known traditional Chinese medicine (TCM) formulas, has been shown to have cardioprotective effects in rats with heart failure (HF) induced by acute myocardial infarction (AMI). However, the mechanisms of its therapeutic effects remain unclear. In this study, we aim to explore the mechanisms of QSYQ in preventing left ventricular remodelling in rats with HF. The anti-apoptosis an anti-inflammation effects of QSYQ were investigated.MethodsSprague–Dawley (SD) rats were randomly divided into 4 groups: sham group, model group, QSYQ treatment group and aspirin group. Heart failure model was induced by ligation of left anterior descending (LAD) coronary artery. 28 days after surgery, hemodynamics were detected. Echocardiography was adopted to evaluate heart function. TUNEL assay was applied to assess myocardial apoptosis rates. Protein expressions of cyclooxygenase1 and 2 (COX1and COX2), Fas ligand (FasL), P53 and MDM2 were measured by western-blot. RT-PCR was applied to detect expressions of our subtype receptors of PGE2 (EP1, 2, 3, and 4).ResultsUltrasonography showed that EF and FS values decreased significantly and abnormal hemodynamic alterations were observed in model group compared to sham group. These indications illustrated that HF models were successfully induced. Levels of inflammatory cytokines (TNF-α and IL-6) in myocardial tissue were up-regulated in the model group as compared to those in sham group. Western-blot analysis showed that cyclooxygenase 2, which is highly inducible by inflammatory cytokines, increased significantly. Moreover, RT-PCR showed that expressions of EP2 and EP4, which are the receptors of PGE2, were also up-regulated. Increased expressions of apoptotic pathway factors, including P53 and FasL, might be induced by the binding of PGE2 with EP2/4. MDM2, the inhibitor of P53, decreased in model group. TUNEL results manifested that apoptosis rates of myocardial cells increased in the model group. After treatment with QSYQ, expressions of inflammatory factors, including TNF-α, IL-6 and COX2, were reduced. Expressions of EP2 and EP4 receptors also decreased, suggesting that PGE2-mediated apoptosis was inhibited by QSYQ. MDM2 was up-regulated and P53 and FasL in the apoptotic pathway were down-regulated. Apoptosis rates in myocardial tissue in the QSYQ group decreased compared with those in the model group.ConclusionsQSYQ exerts cardiac protective efficacy mainly through inhibiting the inflammatory response and down-regulating apoptosis. The anti-inflammatory and anti-apoptosis efficacies of QSYQ are probably achieved by inhibition of COXs-induced P53/FasL pathway. These findings provide experimental evidence for the beneficial effects of QSYQ in the clinical application for treating patients with HF.Electronic supplementary materialThe online version of this article (doi:10.1186/s12906-015-0869-z) contains supplementary material, which is available to authorized users.

Salidroside Mitigates Sepsis-Induced Myocarditis in Rats by Regulating IGF-1/PI3K/Akt/GSK-3β Signaling.

Sepsis-induced myocardial injury (SIMI) is caused by various mechanisms. The aim of this study was to investigate the effects of salidroside (Sal) on SIMI and its mechanisms in rats. The sepsis model was established by intraperitoneal injection of lipopolysaccharide (LPS) (15mg/kg in sterile saline). Sal decreased the serum levels of creatine kinase (CK), lactate dehydrogenase (LDH), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β), whereas the expressions of insulin-like growth factor-1 (IGF-1) signaling-related proteins, such as IGF-1 and its corresponding receptor (IGF-1R), phosphatidylinositol 3-kinase (PI3K), p-PI3K, Akt, p-Akt, and glycogen synthase kinase-3β (GSK-3β), in the heart were decreased with Sal pretreatment. Mitigated myocardial cell swelling, degeneration, loss of transverse striations, and inflammatory cell infiltration were also observed in the LPS + Sal groups. Thus, Sal is assumed to exert pronounced cardioprotective effects in rats subjected to LPS, probably through regulation of IGF-1/PI3K/Akt/GSK-3β signaling.