It has been demonstrated that the anti-oxidative and cardioprotective effects of melatonin are, at least in part, mediated by its membrane receptors. However, the direct downstream signaling remains unknown. We previously found that melatonin ameliorated myocardial ischemia-reperfusion (MI/R) injury in diabetic animals, although the underlying mechanisms are also incompletely understood. This study was designed to determine the role of melatonin membrane receptors in melatonin's cardioprotective actions against diabetic MI/R injury with a focus on cGMP and its downstream effector PKG. Streptozotocin-induced diabetic Sprague-Dawley rats and high-glucose medium-incubated H9c2 cardiomyoblasts were utilized to determine the effects of melatonin against MI/R injury. Melatonin treatment preserved cardiac function and reduced oxidative damage and apoptosis. Additionally, melatonin increased intracellular cGMP level, PKGIα expression, p-VASP/VASP ratio and further modulated myocardial Nrf-2-HO-1 and MAPK signaling. However, these effects were blunted by KT5823 (a selective inhibitor of PKG) or PKGIα siRNA except that intracellular cGMP level did not changed significantly. Additionally, our in vitro study showed that luzindole (a nonselective melatonin membrane receptor antagonist) or 4P-PDOT (a selective MT receptor antagonist) not only blocked the cytoprotective effect of melatonin, but also attenuated the stimulatory effect of melatonin on cGMP-PKGIα signaling and its modulatory effect on Nrf-2-HO-1 and MAPK signaling. This study showed that melatonin ameliorated diabetic MI/R injury by modulating Nrf-2-HO-1 and MAPK signaling, thus reducing myocardial apoptosis and oxidative stress and preserving cardiac function. Importantly, melatonin membrane receptors (especially MT receptor)-dependent cGMP-PKGIα signaling played a critical role in this process.
Diallyl trisulfide (DATS) protects against apoptosis during myocardial ischemia-reperfusion (MI/R) injury in diabetic state, although the underlying mechanisms remain poorly defined. Previously, we and others demonstrated that silent information regulator 1 (SIRT1) activation inhibited oxidative stress and endoplasmic reticulum (ER) stress during MI/R injury. We hypothesize that DATS reduces diabetic MI/R injury by activating SIRT1 signaling. Streptozotocin (STZ)-induced type 1 diabetic rats were subjected to MI/R surgery with or without perioperative administration of DATS (40 mg/kg). We found that DATS treatment markedly improved left ventricular systolic pressure and the first derivative of left ventricular pressure, reduced myocardial infarct size as well as serum creatine kinase and lactate dehydrogenase activities. Furthermore, the myocardial apoptosis was also suppressed by DATS as evidenced by reduced apoptotic index and cleaved caspase-3 expression. However, these effects were abolished by EX527 (the inhibitor of SIRT1 signaling, 5 mg/kg). We further found that DATS effectively upregulated SIRT1 expression and its nuclear distribution. Additionally, PERK/eIF2α/ATF4/CHOP-mediated ER stress-induced apoptosis was suppressed by DATS treatment. Moreover, DATS significantly activated Nrf-2/HO-1 antioxidant signaling pathway, thus reducing Nox-2/4 expressions. However, the ameliorative effects of DATS on oxidative stress and ER stress-mediated myocardial apoptosis were inhibited by EX527 administration. Taken together, these data suggest that perioperative DATS treatment effectively ameliorates MI/R injury in type 1 diabetic setting by enhancing cardiac SIRT1 signaling. SIRT1 activation not only upregulated Nrf-2/HO-1-mediated antioxidant signaling pathway but also suppressed PERK/eIF2α/ATF4/CHOP-mediated ER stress level, thus reducing myocardial apoptosis and eventually preserving cardiac function.
RA is effective for the surgical treatment of long-standing AF associated with rheumatic valve disease. Though vagal denervation helped to maintain a stable sinus rhythm at an early stage, there was no additional benefit after the 1st year of follow-up.
Anomalous connection of the coronary artery to the pulmonary artery (ACAPA) has a low incidence rate in older children and adults. The aim of this article was to evaluate the outcome of treating ACAPA with aortic implantation in older children and adults. We included 21 patients (9 children and 12 adults) with ACAPA in our hospital between January 1991 and January 2015. Among these patients, 19 had anomalous connection of the left coronary artery to the pulmonary artery, 2 had anomalous connection of the right coronary artery to the pulmonary artery (ARCAPA). All of the patients underwent aortic implantation, aged 4 to 62 years (median, 18). The mean left ventricular ejection fraction (LVEF) was 55.9 ± 7.6% (<50% in 4). Eleven patients underwent direct aortic implantation (including two ARCAPAs), while 10 patients underwent tubular implantation. Eleven patients had varying degrees of mitral regurgitation, while mitral valve plasty or replacement was performed in six patients (severe mitral regurgitation) concurrently. There was no early mortality. Follow-up observation was performed in all 21 patients, with a mean follow-up time of 6.4 ± 5.6 years (ranging from 0.5 to 23 years). Two patients died due to noncardiac reasons 1 and 10 years after operation, respectively. Seven patients had mild mitral regurgitation, while no patients had moderate or severe mitral regurgitation after operations. The postoperative mean LVEF was not improved at 54.7 ± 7.0%, > 0.05. Among the multiple surgical strategies for the treatment of ACAPA, aortic implantation was used commonly in older children and adults, while mitral valve repair can be performed concurrently.
BackgroundThe successful treatment of military combat casualties with penetrating injuries is significantly dependent on the time needed to get the patient to an adequate treatment facility. Profound hypothermia-induced suspended animation for delayed resuscitation (SADR) is a novel approach for inducing cardiac arrest and buying additional time for such injuries. However, the time used to safely administer circulatory arrest (CA) is controversial. The goal of this study was to evaluate the safety of hypothermia-induced SADR over 90 and 120 min time intervals.MethodsSixteen male BAMA minipigs were randomized into two groups: CA90 group (90 min, n = 8) and CA120 group (120 min, n = 8). Cannulation of the right common carotid arteries and internal jugular veins was performed to establish cardiopulmonary bypass for each animal. Through the perfusion of cold organ preservation solution (OPS), cardioplegia and profound hypothermia (15 °C) were induced. After CA, cardiopumonary bypass (CPB) was restarted, and the animals were gradually re-warmed and resuscitated. The animals were assisted with ventilators until spontaneous breathing was achieved. The index of hemodynamic perioperative serum chemistry values [alanine transaminase (ALT), aspartate aminotransferase (AST), creatinine (CR), lactic dehydrogenase (LDH) and troponin T (TnT)] and survival were observed from pre-operation to 7 days post-operation.ResultsFifteen animals were enrolled in the experiment, while 1 animal in CA120 group died from surgical error. All 8 animals in CA90 group recovered, with only 1 animal displaying mild disability. However, in CA120 group, only 2 animals survived with severe disability, and the other 5 animals died after 2 days post-operation. In CA90 group, the perioperative serum chemistry values increased at 1 day post-operation (ALT 84.43 ± 18.65 U/L; AST 88.99 ± 23.19 U/L; Cr 87.90 ± 24.49 μmol/L; LDH 1894.13 ± 322.26 U/L; TnT 0.849 ± 0.135 ng/ml) but decreased to normal or almost normal levels at 7 days post-operation (ALT 52.48 ± 9.04 U/L; AST 75.23 ± 21.46 U/L; Cr 82.69 ± 18.41 μmol/L; LDH 944.67 ± 834.32 U/L; TnT 0.336 ± 0.076 ng/ml).ConclusionsProfound hypothermia-induced SADR is an effective method for inducing cardiac arrest. Our results indicate that inducing CA for 90 min (at 15 °C) is safer than doing so for 120 min. Our results indicate that 120 min of CA at 15 °C is dangerous and can result in high mortality and severe neurological complications. Further experimentation is needed to determine whether 120 min of CA at temperatures lower than 15 °C can lead to safe recovery.
Myocardial ischemia/reperfusion (I/R) injury is a potential complication of ischemic heart disease after recanalization. One of the primary reasons for I/R injury is the excessive accumulation of reactive oxygen species (ROS) in cardiomyocytes. Verapamil, a classic calcium channel blocker, has the potential to mitigate I/R-evoked oxidative stress. However, the underlying mechanisms have not been fully elucidated. SIRT1 is an essential regulator of I/R and offers resistance to oxidative stress arising from I/R. It is still inconclusive if verapamil can reduce myocardial I/R-triggered oxidative damage through modulating SIRT1 antioxidant signaling. To verify our hypothesis, the H9c2 cardiomyocytes and the mice were treated with verapamil and then exposed to hypoxia/reoxygenation (H/R) or I/R in the presence or absence of the SIRT1 inhibitor EX527. As expected, verapamil stimulated SIRT1 antioxidant signaling evidenced by upregulation of SIRT1, FoxO1, SOD2 expressions and downregulation of Ac-FoxO1 expression in vitro and in vivo. In addition, verapamil remarkably suppressed H/R and I/R-induced oxidative stress proven by declined ROS level and MDA content. The cardioprotective actions of verapamil via SIRT1 were further confirmed in the experiments with the presence of the specific SIRT1 inhibitor EX527. We demonstrated that verapamil alleviated myocardial I/R-evoked oxidative stress partially via activation of SIRT1 antioxidant signaling. Subsequently, verapamil protected against cardiac dysfunction and myocardial infarction accompanied by oxidative stress.
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