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      Dexmedetomidine protects H9c2 cardiomyocytes against oxygen-glucose deprivation/reoxygenation-induced intracellular calcium overload and apoptosis through regulating FKBP12.6/RyR2 signaling

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          Intracellular calcium ([Ca 2+]i) overload is a major cause of cell injury during myocardial ischemia/reperfusion (I/R). Dexmedetomidine (DEX) has been shown to exert anti-inflammatory and organ protective effects. This study aimed to investigate whether pretreatment with DEX could protect H9c2 cardiomyocytes against oxygen-glucose deprivation/reoxygenation (OGD/R) injury through regulating the Ca 2+ signaling.


          H9c2 cardiomyocytes were subjected to OGD for 12 h, followed by 3 h of reoxygenation. DEX was administered 1 h prior to OGD/R. Cell viability, lactate dehydrogenase (LDH) release, level of [Ca 2+]i, cell apoptosis, and the expression of 12.6-kd FK506-binding protein/ryanodine receptor 2 (FKBP12.6/RyR2) and caspase-3 were assessed.


          Cells exposed to OGD/R had decreased cell viability, increased LDH release, elevated [Ca 2+]i level and apoptosis rate, down-regulated expression of FKBP12.6, and up-regulated expression of phosphorylated-Ser2814-RyR2 and cleaved caspase-3. Pretreatment with DEX significantly blocked the above-mentioned changes, alleviating the OGD/R-induced injury in H9c2 cells. Moreover, knockdown of FKBP12.6 by small interfering RNA abolished the protective effects of DEX.


          This study indicates that DEX pretreatment protects the cardiomyocytes against OGD/R-induced injury by inhibiting [Ca 2+]i overload and cell apoptosis via regulating the FKBP12.6/RyR2 signaling. DEX may be used for preventing cardiac I/R injury in the clinical settings.

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          The effects of increasing plasma concentrations of dexmedetomidine in humans.

          This study determined the responses to increasing plasma concentrations of dexmedetomidine in humans. Ten healthy men (20-27 yr) provided informed consent and were monitored (underwent electrocardiography, measured arterial, central venous [CVP] and pulmonary artery [PAP] pressures, cardiac output, oxygen saturation, end-tidal carbon dioxide [ETCO2], respiration, blood gas, and catecholamines). Hemodynamic measurements, blood sampling, and psychometric, cold pressor, and baroreflex tests were performed at rest and during sequential 40-min intravenous target infusions of dexmedetomidine (0.5, 0.8, 1.2, 2.0, 3.2, 5.0, and 8.0 ng/ml; baroreflex testing only at 0.5 and 0.8 ng/ml). The initial dose of dexmedetomidine decreased catecholamines 45-76% and eliminated the norepinephrine increase that was seen during the cold pressor test. Catecholamine suppression persisted in subsequent infusions. The first two doses of dexmedetomidine increased sedation 38 and 65%, and lowered mean arterial pressure by 13%, but did not change central venous pressure or pulmonary artery pressure. Subsequent higher doses increased sedation, all pressures, and calculated vascular resistance, and resulted in significant decreases in heart rate, cardiac output, and stroke volume. Recall and recognition decreased at a dose of more than 0.7 ng/ml. The pain rating and mean arterial pressure increase to cold pressor test progressively diminished as the dexmedetomidine dose increased. The baroreflex heart rate slowing as a result of phenylephrine challenge was potentiated at both doses of dexmedetomidine. Respiratory variables were minimally changed during infusions, whereas acid-base was unchanged. Increasing concentrations of dexmedetomidine in humans resulted in progressive increases in sedation and analgesia, decreases in heart rate, cardiac output, and memory. A biphasic (low, then high) dose-response relation for mean arterial pressure, pulmonary arterial pressure, and vascular resistances, and an attenuation of the cold pressor response also were observed.
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            JAK2/STAT3 activation by melatonin attenuates the mitochondrial oxidative damage induced by myocardial ischemia/reperfusion injury.

            Ischemia/reperfusion injury (IRI) is harmful to the cardiovascular system and causes mitochondrial oxidative stress. Numerous data indicate that the JAK2/STAT3 signaling pathway is specifically involved in preventing myocardial IRI. Melatonin has potent activity against IRI and may regulate JAK2/STAT3 signaling. This study investigated the protective effect of melatonin pretreatment on myocardial IRI and elucidated its potential mechanism. Perfused isolated rat hearts and cultured neonatal rat cardiomyocytes were exposed to melatonin in the absence or presence of the JAK2/STAT3 inhibitor AG490 or JAK2 siRNA and then subjected to IR. Melatonin conferred a cardio-protective effect, as shown by improved postischemic cardiac function, decreased infarct size, reduced apoptotic index, diminished lactate dehydrogenase release, up-regulation of the anti-apoptotic protein Bcl2, and down-regulation of the pro-apoptotic protein Bax. AG490 or JAK2 siRNA blocked melatonin-mediated cardio-protection by inhibiting JAK2/STAT3 signaling. Melatonin exposure also resulted in a well-preserved mitochondrial redox potential, significantly elevated mitochondrial superoxide dismutase (SOD) activity, and decreased formation of mitochondrial hydrogen peroxide (H2 O2 ) and malondialdehyde (MDA), which indicates that the IR-induced mitochondrial oxidative damage was significantly attenuated. However, this melatonin-induced effect on mitochondrial function was reversed by AG490 or JAK2 siRNA treatment. In summary, our results demonstrate that melatonin pretreatment can attenuate IRI by reducing IR-induced mitochondrial oxidative damage via the activation of the JAK2/STAT3 signaling pathway. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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              Calmodulin kinase II-mediated sarcoplasmic reticulum Ca2+ leak promotes atrial fibrillation in mice.

              A trial fibrillation (AF), the most common human cardiac arrhythmia, is associated with abnormal intracellular Ca2+ handling. Diastolic Ca2+ release from the sarcoplasmic reticulum via "leaky" ryanodine receptors (RyR2s) is hypothesized to contribute to arrhythmogenesis in AF, but the molecular mechanisms are incompletely understood. Here, we have shown that mice with a genetic gain-of-function defect in Ryr2 (which we termed Ryr2R176Q/+ mice) did not exhibit spontaneous AF but that rapid atrial pacing unmasked an increased vulnerability to AF in these mice compared with wild-type mice. Rapid atrial pacing resulted in increased Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation of RyR2, while both pharmacologic and genetic inhibition of CaMKII prevented AF inducibility in Ryr2R176Q/+ mice. This result suggests that AF requires both an arrhythmogenic substrate (e.g., RyR2 mutation) and enhanced CaMKII activity. Increased CaMKII phosphorylation of RyR2 was observed in atrial biopsies from mice with atrial enlargement and spontaneous AF, goats with lone AF, and patients with chronic AF. Genetic inhibition of CaMKII phosphorylation of RyR2 in Ryr2S2814A knockin mice reduced AF inducibility in a vagotonic AF model. Together, these findings suggest that increased RyR2-dependent Ca2+ leakage due to enhanced CaMKII activity is an important downstream effect of CaMKII in individuals susceptible to AF induction.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                02 September 2019
                : 13
                : 3137-3149
                [1 ]Department of Anesthesiology, First Affiliated Hospital of Soochow University , Suzhou, Jiangsu 215006, People’s Republic of China
                [2 ]Department of Anesthesiology, Affiliated Suzhou Hospital of Nanjing Medical University , Suzhou, Jiangsu 215008, People’s Republic of China
                [3 ]Department of Anesthesiology and Pain Medicine, University of California Davis Health System , Sacramento, CA 95817, USA
                Author notes
                Correspondence: Fu-Hai Ji; Ke PengDepartment of Anesthesiology, First Affiliated Hospital of Soochow University , 188 Shizi Street, Suzhou, Jiangsu215006, People’s Republic of ChinaTel +86 5 126 778 0055; +86 5 126 778 0159Email jifuhaisuda@163.com; pengke0422@163.com

                These authors contributed equally to this work

                © 2019 Yuan et al.

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                Page count
                Figures: 8, Tables: 2, References: 55, Pages: 13
                Original Research


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