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• Dexmedetomidine induces protection by decreasing myocardial infarction and apoptosis of H9C2 cells. • miR-146a-3p is downregulated after myocardial ischemia/reperfusion and H9C2 anoxia/reoxygenation. • Involve of miR-146a-3p/IRAK1/TRAF6/NF-κB axis in dexmedetomidine-induced cardioprotection. Myocardial ischemia/reperfusion (I/R) injury is a common cause of mortality. Cardiac miR-146a is emerging as a potent regulator of myocardial function. Dexmedetomidine preconditioning provides cardioprotective effects, of which mechanisms related to miR-146a-3p are unclear. A myocardial I/R model in rats and a cellular anoxia/reoxygenation (A/R) model in H9C2 cells were established and preconditioned with dexmedetomidine or not. H9C2 cells were transfected with mimics, inhibitor, or negative controls of miR-146a-3p, and siRNAs of IRAK1 or TRAF6. Relative expressions of miR-146a-3p were determined by quantitative real-time polymerase chain reaction. The apoptosis rates and reactive oxygen species (ROS) levels in H9C2 cells were examined by flow cytometry. Protein expressions of IRAK1, TRAF6, cleaved Caspase-3, BAX, BCL-2, NF-κB p65, phosphorylated NF-κB p65 (p-NF-κB p65), IκBα, and phosphorylated IκBα (p-IκBα) in H9C2 cells were detected by Western blot. Dexmedetomidine decreased myocardial infarction size and apoptosis rates of H9C2 cells. Dexmedetomidine upregulated expression of miR-146a-3p. Dexmedetomidine significantly decreased protein expressions of IRAK1, TRAF6, cleaved Caspase-3, BAX, and NF-κB p65, but increased expressions of BCL-2 in H9C2 cells. miR-146a-3p overexpression strengthened the anti-apoptotic effect induced by dexmedetomidine in H9C2 cells via decreasing protein levels of IRAK1, TRAF6, cleaved Caspase-3, BAX, NF-κB p65, p-NF-κB p65, and p-IκBα and increasing protein level of BCL-2. Downregulation of miR-146a-3p reversed the changes in these proteins in H9C2 cells. Expressions of NF-κB p65 and p-NF-κB p65 were further decreased following knockdown of IRAK1 or TRAF6. ROS emission was significantly increased after A/R, while significantly decreased following dexmedetomidine preconditioning in H9C2 cells transfected with siIRAK1 or siTRAF6. miR-146a-3p targeting IRAK1 and TRAF6 through inhibition of NF-κB signaling pathway and ROS emission is involved in cardioprotection induced by dexmedetomidine pretreatment. [ABSTRACT FROM AUTHOR]

Cardiovascular disease, particularly ischemic heart disease (IHD), is the leading cause of mortality worldwide. Bisphenol A (BPA) is considered an endocrine disruptor and obesogen, present in numerous products of daily use. The aim of this study was to assess the potential association of serum BPA concentrations and the risk of incident IHD in a sub-cohort of the Spanish European Prospective Investigation into Cancer and Nutrition (EPIC). We designed a case-cohort study within the EPIC-Spain cohort. The population consisted of 4636 participants from 4 EPIC-Spain centers (946 IHD cases and 3690 sub-cohort participants). BPA exposure was assessed by means of chemical analyses of serum samples collected at recruitment. Follow-up was performed by linking with national and regional databases and reviewing patients' clinical records. Cox Proportional Hazards Models were used for the statistical analyses. Median follow-up time was 16 years and 70% of the participants showed detectable BPA values (>0.2 ng/ml). Geometric mean (GM) values of cases and sub-cohort were 1.22 ng/ml vs 1.19 ng/ml respectively (p = 0.90). Cox regression models showed no significant association of BPA serum levels and IHD, acute myocardial infarction or angina pectoris risk. We evidenced a similar percentage of detection of BPA among cases and sub-cohort participants from our population, and no clear association with IHD risk was observed. However, further investigation is needed to understand the influence of BPA on IHD risk. • BPA concentrations were quantified in serum from 946 adults with ischemic heart disease. • There was a higher proportion of overweight and obesity in cases than in the sub-cohort. • BPA serum concentration was higher in cases than in participants of the sub-cohort. • We observed no increased risk on IHD with BPA exposure. [ABSTRACT FROM AUTHOR]

• Both total saponins from Panacis majoris Rhizoma (TSPJ) and the degradation products of TSPJ (DTSPJ) were prepared. • The main constituents of TSPJ and DTSPJ were analyzed and the possible mechanisms were also investigated. • The protection of DTSPJ against myocardial ischemia-reperfusion injury was a little stronger than those of TSPJ. • DTSPJ represents a promising drug candidate for treating ischemic heart disease. Panacis majoris Rhizoma, which is a member of herbal medicine, is known for many years to remove blood stasis, promote blood circulation, and enrich the blood. The active ingredients of this plant are mainly attributed to saponins. The total saponins from Panacis majoris Rhizoma (TSPJ), and the degradation products of TSPJ (DTSPJ), were designed in this study to compare the protective effects on myocardial ischemia-reperfusion injury, and the aim of this approach is to discover more effective agents for the treatment of ischemic heart diseases. We analyzed the main constituents of TSPJ and DTSPJ, aiming to make clear which saponins played important roles in this protective effect, and also investigated the possible mechanisms. DTSPJ was prepared by the method of alkaline hydrolysis. High performance liquid chromatography (HPLC) were used to analyze the main chemical constituents of TSPJ and DTSPJ, which were isolated by chromatographic techniques and identified by comparison with the Nuclear Magnetic Resonance (NMR) data in reported literature. Male Wistar rats were randomized to sham-operated group, ischemia-reperfusion group, three TSPJ (50, 100 and 200 mg/kg) groups, three DTSPJ (50, 100 and 200 mg/kg) groups, and isosorbide dinitrate tablet (5.0 mg/kg) group. The rats in all groups were intragastrically administrated once per day for three successive days. The establishment of the model of myocardial ischemia-reperfusion injury was used the following method: firstly, the left coronary artery of experimental rat was ligated for 30 min and then reperfused for 120 min. Then the myocardial infarct size, hemorheological and biochemical parameters, whole blood viscosity, plasma viscosity, platelet adhesion rate, platelet aggregation and histopathology changes were assessed. Five C 3 ,C 28 -bidesmosidic oleanane-type saponins and ginsenoside Rd were the main constituents of TSPJ, and their total content in TSPJ was 79.2 %. The main constituents of DTSPJ were five C 3 -monodesmosidic oleanane-type saponins and ginsenoside Rd, and their total content in DTSPJ was 72.6 %. The HPLC analysis revealed that the five C 3 ,C 28 -bidesmosidic oleanane-type saponins in TSPJ were completely turned into five C 3 -monodesmosidic oleanane-type saponins in DTSPJ through the method of alkaline hydrolysis, but ginsenoside Rd remained unchanged. Both TSPJ and DTSPJ could significantly reduced myocardial infarct size, and improved heart function, and lowered the activities of aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and creatine kinase isoenzymes (CK-MB), and malonyldialdehyde (MDA) content, as well as the levels of whole blood viscosity, plasma viscosity, platelet adhesion rate, and platelet aggregation; on the contrary, both the level of glutathione peroxidase (GSH-Px) and the activity of superoxide dismutase (SOD) were notablely increased. The results of histopathological examination further supported the cardioprotective effects of TSPJ and DTSPJ. Both TSPJ and DTSPJ can guard cardiomyocytes against myocardial ischemia-reperfusion injury. The underlying mechanisms may be closely related to its enhancing anti-oxidative properties, modifying blood viscosity, and inhibiting platelet aggregation and platelet adhesion. As a whole, the protection of DTSPJ against myocardial ischemia-reperfusion injury was a little stronger than those of TSPJ. The results display the prospect of DTSPJ as a drug candidate for treating ischemic heart disease. [ABSTRACT FROM AUTHOR]

Myocardial ischemia/reperfusion (I/R) injury is a common consequence of restored blood supply after acute myocardial infarction (AMI), but its underlying mechanisms remain largely elusive. In this study, we aimed to investigate the functional role of long non-coding RNA PVT1 in hypoxia/reoxygenation (H/R)-treated AC16 cardiomyocytes. Our experimental results demonstrated that H/R treatment impaired the viability and increased the apoptosis of AC16 cells, and knockdown of PVT1 blocked the H/R injury. Besides, PVT1 knockdown also reduced excessive autophagy in H/R-treated AC16 cells. Furthermore, we confirmed that PVT1 might serve as a ceRNA for miR-186 in AC16 cells, and rescue experiments showed that miR-186 inhibition blocked the effects of PVT1 knockdown in H/R-treated AC16 cells. In summary, this study implied that PVT1 might be a promising therapeutic target for treating myocardial I/R injury. [ABSTRACT FROM AUTHOR]

• Sevoflurane and propofol have previously been implicated in myocardial protection. • In a non-conditioning protocol only sevoflurane reduced myocardial ischemic injury. • Sevoflurane as opposed to propofol anesthesia preserved mitochondrial respiration. • Propofol anesthesia impeded mitochondrial function during myocardial ischemia. • A higher portion of complex I was in its deactive form during ischemia and sevoflurane anesthesia. Pharmacological interventions reducing myocardial ischemia and reperfusion (I/R) injury include the administration of anesthetics. Both sevoflurane as well as propofol have been shown to elicit cardiac protection via distinct molecular mechanisms. We investigated the hypothesis that sevoflurane in contrary to propofol anesthesia elicits cardiac protection against I/R-injury via mitochondrial mechanisms of disease. Male New Zealand white rabbits (n = 42) were subjected 30 min of coronary artery occlusion followed by 3 h of reperfusion. After induction with pentobarbital, the animals either received sevoflurane or propofol to maintain general anesthesia. Infarct size was determined gravimetrically after triphenyltetrazolium chlorid-staining. Cardiac mitochondria were isolated and mitochondrial oxygen consumption was measured using a Clark electrode. Mitochondrial respiratory chain complex activities (I-IV) were analyzed utilizing specific assays. Data are mean ± SD. Sevoflurane anesthesia significantly decreased the resulting myocardial infarct size compared to propofol anesthesia (p = 0.0275 vs. propofol). Mitochondria from animals receiving propofol anesthesia showed a significantly reduced mitochondrial respiratory control ratio (p = 0.01909 vs. sham) and impaired activities of respiratory complex I (p = 0.0147 vs. sham; p < 0.01 vs. sevoflurane) as well as respiratory complex IV (p = 0.0181 vs. sham). Mitochondrial dysfunction was absent in sevoflurane anesthesized animals. Furthermore, a significantly higher portion of complex I was found to be in its deactive form during I/R-injury in animals receiving sevoflurane anesthesia (p = 0.0123 vs. propofol). Sevoflurane as opposed to propofol anesthesia preserved mitochondrial respiration and elicited cardiac protection against I/R-injury. [ABSTRACT FROM AUTHOR]

• Targeted drug delivery could improve myocyte viability after an ischemic injury. • MIBI is captured by the myocyte and can be employed as a drug carrier. • MIBI-conjugated gold nanoparticles are stable in solution and have no organic toxicity. • The gold-targeted delivery system decreased IL-6 in rat heart after myocardial ischemia. • MIBI-conjugated gold nanoparticles decrease glutathione oxidation in rat heart after myocardial ischemia. The tissue response to acute myocardial infarction (AMI) is key to avoiding heart complications due to inflammation, mitochondrial dysfunction, and oxidative stress. Antioxidant and anti-inflammatory agents can minimize the effects of AMI. This study investigated the role of 2-methoxy-isobutyl-isonitrile (MIBI)-associated gold nanoparticles (AuNP) on reperfusion injury after ischemia and its effect on cardiac remodeling in an experimental AMI model. Three-month-old Wistar rats were subjected to a temporary blockade of the anterior descending artery for 30 min followed by reperfusion after 24 h and 7 days by intraventricularly administering 0.4, 1.3, and 3 mg/kg AuNP-MIBI. The cardiac toxicity and renal and hepatic function levels were determined, and the infarct and peri-infarct regions were surgically removed for histopathology, analysis of inflammation from oxidative stress, and echocardiography. MIBI-conjugated AuNP promoted changes in oxidative stress and inflammation depending on the concentrations used, suggesting promising applicability for therapeutic purposes. [ABSTRACT FROM AUTHOR]

Ginsenoside Rb1 (GRb1) is known to play an effective protection on myocardial infarction, yet its therapeutic mechanism on myocardial ischemia/reperfusion (I/R) injury has remained obscure. Here we sought to investigate the protective mechanism of GRb1 preconditioning on myocardial I/R injury in rats. We report here that GRb1 preconditioning could improve myocardial I/R injury induced-cardiac functions including LVDP, -dp/dt min and + dp/dt max; however, the heart rate (HR) was maintained at a level comparable to the I/R group. Additionally, in I/R injury group given GRb1 preconditioning, release of myocardial enzymes (CK-MB and Trop l) and CtsB was decreased. Moreover, GRb1 decreased the expression of apoptotic related proteins e.g. cleaved-caspase 3; however, the ratio of Bcl-2/Bax related to anti-apoptosis was decreased. The study was extended by injecting rapamycin intraperitoneally before GRb1 pretreatment. Thus, mTOR pathway was significantly upregulated after GRb1 pretreatment when compared with I/R. Remarkably, the anti-apoptosis protection of GRb1 pretreatment was attenuated by rapamycin. Furthermore, GRb1 effectively reduced the infarct size thus supporting its role in anti-myocardial I/R injury. It is concluded that GRb1 preconditioning can ameliorate myocardial I/R injury as manifested by the improvement of cardiac function indices; moreover, release of myocardial enzymes, namely, CK-MB, Trop l and CtsB was reduced. More importantly, we have shown that the protective effect of GRb1 against I/R injury induced cardiomyocyte apoptosis is associated with the activation of mTOR signal pathway as evident by the use of rapamycin. [ABSTRACT FROM AUTHOR]

Metoprolol (Met) is widely applied in the treatment of myocardial infarction and coronary heart disease in clinic. However, the metabolic network in vivo affected by Met manipulation is still unclear and it's therapeutic molecular mechanisms were remained to be furthered elucidated except β1 adrenergic receptor. Myocardial infarction (MI) was induced by permanent CAL for 24 h in ICR mice. Myocardial infarct size, biochemical indicators such as creatine kinase (CK), lactate dehydrogenase (LDH), C-reactive Protein (CRP), tumor necrosis factor-α (TNF-α) and cardiac troponin I(cTn-I), cardiac function and myocardial pathological changes were detected to ensure the improvement of Met on MI. Subsequently, the significantly changed endogenous metabolites and the network in both serum and urine were screened and constructed through metabolomics by using HPLC-Q-TOF/MS. Finally, the potential regulatory enzymes that could be the possible new therapeutic targets of Met were selected and validated by western blotting and immunohistochemistry based on the screened differential metabolites and the enrichment analysis. Met effectively reduced the infarct size of myocardial infarction mice, improved the biochemical indicators, and ameliorated the cardiac function and pathological conditions. Our study further found that Met could regulate the pathways of glycine, serine and threonine metabolism, cysteine and methionine metabolism, purine and pyrimidine metabolism under the pathological conditions of MI. Moreover, several regulatory enzymes involved GATM, CSE and NT5E were demonstrated to be regulated by Met. This study constructed the regulatory metabolic network map of Met, elucidated the endogenous metabolic pathway regulated by Met, and validated the new potential therapeutic targets of Met in MI, which might provide a further reference for the clinical application of Met. [ABSTRACT FROM AUTHOR]