GDF11 Alleviates Pathological Myocardial Remodeling in Diabetic Cardiomyopathy Through SIRT1-Dependent Regulation of Oxidative Stress and Apoptosis.

Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor ß superfamily that alleviates cardiac hypertrophy, myocardial infarction, and vascular injury by regulating oxidative stress, inflammation, and cell survival. However, the roles and underlying mechanisms of GDF11 in diabetic cardiomyopathy (DCM) remain largely unknown. In this study, we sought to determine whether GDF11 could prevent DCM. After establishing a mouse model of diabetes by administering a high-fat diet and streptozotocin, intramyocardial injection of an adeno-associated virus was used to achieve myocardium-specific GDF11 overexpression. GDF11 remarkably improved cardiac dysfunction and interstitial fibrosis by reducing the levels of reactive oxygen species and protecting against cardiomyocyte loss. Mechanistically, decreased sirtuin 1 (SIRT1) expression and activity were observed in diabetic mice, which was significantly increased after GDF11 overexpression. To further explore how SIRT1 mediates the role of GDF11, the selective inhibitor EX527 was used to block SIRT1 signaling pathway, which abolished the protective effects of GDF11 against DCM. In vitro studies confirmed that GDF11 protected against H9c2 cell injury in high glucose and palmitate by attenuating oxidative injury and apoptosis, and these effects were eliminated by SIRT1 depletion. Our results demonstrate for the first time that GDF11 protects against DCM by regulating SIRT1 signaling pathway.

Clinical profiles and outcomes of acute type A aortic dissection and intramural hematoma in the current era: lessons from the first registry of aortic dissection in China.

BACKGROUND: Acute type A aortic dissection (ATAAD) and acute type A intramural hematoma (ATAIMH) are life-threatening diseases with high mortality. To better understand their clinical features in the Chinese population, we analyzed the data from the first Registry of Aortic Dissection in China (Sino-RAD) to promote the understanding and management of the diseases. METHODS: All patients with ATAAD and ATAIMH enrolled in Sino-RAD from January 1, 2012 to December 31, 2016 were involved. The data of patients' selection, history, symptoms, management, outcomes, and postoperation complications were analyzed in the study. The continuous variables were compared using the Student's t test for normal distributions and the Mann-Whitney U test for non-normal distributions. Categorical variables were compared using the Chi-square test or Fisher exact test. RESULTS: A total of 1582 patients with ATAAD and 130 patients with ATAIMH were included. The mean age of all patients was 48.4 years. Patients with ATAAD were significantly younger than patients with ATAIMH (48.9 years vs. 55.6 years, P < 0.001). For the total cohort, males were dominant, but the male ratio of patients with ATAAD was significantly higher compared to those with ATAIMH (P = 0.01). The time range from the onset of symptom to hospitalization was 2.0 days. More patients of ATAIMH had hypertension than that of ATAAD (82.3% vs. 67.6%, P < 0.05). Chest and back pain were the most common clinical symptoms. Computerized tomography (CT) was the most common initial diagnostic imaging modality. 84.7% received surgical treatment and in-hospital mortality was 5.3%. Patients with ATAAD mainly received surgical treatment (89.6%), while most patients with ATAIMH received medical treatment (39.2%) or endovascular repair (35.4%). CONCLUSIONS: Our study suggests that doctors should comprehensively use clinical examination and genetic background screening for patients with ATAAD and ATAIMH and further shorten the time range from symptoms onset to intervention, achieving early diagnosis and treatment, thereby reducing the mortality rate of patients with aortic dissection in China. We should standardize the procedures of aortic dissection treatment and improve people's understanding. Meanwhile, the curing and transferring efficiency should also be improved.

Early risk stratification of acute type A aortic dissection: development and validation of a predictive score.

BACKGROUND: The performance of published preoperative risk scores for acute type A aortic dissection (aTAAD) is suboptimal. So, the predictive power of these scores were externally validated in order to develop and validate a more reliable preoperative score for identification of patients at high risk of mortality. METHODS: Potential preoperative risk variables of consecutively admitted patients with aTAAD were prospectively collected. Seven published risk scores were validated with our dataset. For derivation and internal validation, the original population was divided at a ratio of 7:3. Logistic regression was used to identify variables for the new score. A 50-patient retrospective dataset was used for external validation. The predictive accuracy for post-operative mortality was evaluated using the area under the receiver operating characteristic (AUROC) curve. RESULTS: During the study period, 225 patients with aTAAD were admitted preoperatively. Of these, 209 underwent surgical repair and 29 died postoperatively. The AUROCs of the seven published pre-operative risk scores for post-operative mortality ranged from 0.57 to 0.77. Four variables were derived for the new score system, i.e., Acute myocardial ischemia, Lactate, Iliac arteries involved, and CreatininE (the ALICE score). The AUROCs for post-operative mortality in the derivation, internal and external validation populations were 0.85, 0.88 and 0.83, respectively. At a cutoff value of 3, the ALICE score for post-operative mortality had a sensitivity of 71% to 88% and specificity of 78% to 86%. CONCLUSIONS: The ALICE score comprising four components might help bedside clinicians in early detection of the most severe aTAAD patients.

2,3,5,4'-Tetrahydroxystilbene-2-O-ß-D-glucoside protects murine hearts against ischemia/reperfusion injury by activating Notch1/Hes1 signaling and attenuating endoplasmic reticulum stress.

2,3,5,4'-Tetrahydroxystilbene-2-O-ß-D-glucoside (TSG) is a water-soluble active component extracted from Polygonum multiflorum Thunb. A number of studies demonstrate that TSG exerts cardioprotective effects. Since endoplasmic reticulum (ER) stress plays a key role in myocardial ischemia/reperfusion (MI/R)-induced cell apoptosis, we sought to determine whether modulation of the ER stress during MI/R injury was involved in the cardioprotective action of TSG. Male mice were treated with TSG (60 mg·kg-1·d-1, ig) for 2 weeks and then were subjected to MI/R surgery. Pre-administration of TSG significantly improved post-operative cardiac function, and suppressed MI/R-induced myocardial apoptosis, evidenced by the reduction in the myocardial apoptotic index, serum levels of LDH and CK after 6 h of reperfusion. TSG (0.1-1000 µmol/L) did not affect the viability of cultured H9c2 cardiomyoblasts in vitro, but pretreatment with TSG dose-dependently decreased simulated ischemia/reperfusion (SIR)-induced cell apoptosis. Furthermore, both in vivo and in vitro studies revealed that TSG treatment activated the Notch1/Hes1 signaling pathway and suppressed ER stress, as evidenced by increasing Notch1, Notch1 intracellular domain (NICD), Hes1, and Bcl-2 expression levels and by decreasing p-PERK/PERK ratio, p-eIF2α/eIF2α ratio, and ATF4, CHOP, Bax, and caspase-3 expression levels. Moreover, the protective effects conferred by TSG on SIR-treated H9c2 cardiomyoblasts were abolished by co-administration of DAPT (the Notch1 signaling inhibitor). In summary, TSG ameliorates MI/R injury in vivo and in vitro by activating the Notch1/Hes1 signaling pathway and attenuating ER stress-induced apoptosis.

[Proanthocyanidin protects H9C2 cells against hypoxia/reoxygenation injury via JAK2/STAT3 signaling pathway].

The present study was aimed to investigate the underlying mechanisms of the protective effect of proanthocyanidin (Pro) against hypoxia/reoxygenation (H/R) injury in H9C2 cells with a focus on Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway. H9C2 cells were randomly assigned to 5 groups, including the control group (Con), the H/R-injured group (H/R), the Pro-treated group (H/R+Pro), the JAK2 siRNA-treated group (H/R+Pro+JAK2 siRNA) and the JAK2 siRNA control group (H/R+JAK2 siRNA). The cells were pretreated with Pro (40 µmol/L) for 8 h before 2 h of hypoxia and 4 h of reoxygenation. Cellular viability and apoptosis rate were detected by MTT and TUNEL methods, and superoxide generation was measured. JAK2/STAT3 signaling, oxidative stress markers and endoplasmic reticulum stress markers were also detected by Western blot. We found that Pro treatment significantly improved cellular viability and reduced apoptosis rate in H/R-treated H9C2 cells. In addition, Pro treatment significantly up-regulated the phosphorylation levels of JAK2 and STAT3, down-regulated the superoxide generation, gp91phox, glucose-regulated protein 78 (GRP78), CCAAT/enhancer binding protein homologous protein (CHOP) and caspase-12 expression. However, these protective effects of Pro were all attenuated by JAK2 siRNA administration. Taken together, we demonstrated that Pro protects H9C2 cells against H/R-induced oxidative stress and endoplasmic reticulum stress injury via JAK2/STAT3 signaling pathway.

Berberine protects rat heart from ischemia/reperfusion injury via activating JAK2/STAT3 signaling and attenuating endoplasmic reticulum stress.

AIM: Berberine (BBR), an isoquinoline-derived alkaloid isolated from Rhizoma coptidis, exerts cardioprotective effects. Because endoplasmic reticulum (ER) stress plays a pivotal role in myocardial ischemia/reperfusion (MI/R)-induced apoptosis, it was interesting to examine whether the protective effects of BBR resulted from modulating ER stress levels during MI/R injury, and to define the signaling mechanisms in this process. METHODS: Male rats were treated with BBR (200 mg · kg(-1) · d(-1), ig) for 2 weeks, and then subjected to MI/R surgery. Cardiac dimensions and function were assessed using echocardiography. Myocardial infarct size and apoptosis was examined. Total serum LDH levels and CK activities, superoxide production, MDA levels and the antioxidant SOD activities in heart tissue were determined. An in vitro study was performed on cultured rat embryonic myocardium-derived cells H9C2 exposed to simulated ischemia/reperfusion (SIR). The expression of apoptotic, ER stress-related and signaling proteins were assessed using Western blot analyses. RESULTS: Pretreatment with BBR significantly reduced MI/R-induced myocardial infarct size, improved cardiac function, and suppressed myocardial apoptosis and oxidative damage. Furthermore, pretreatment with BBR suppressed MI/R-induced ER stress, evidenced by down-regulating the phosphorylation levels of myocardial PERK and eIF2α and the expression of ATF4 and CHOP in heart tissues. Pretreatment with BBR also activated the JAK2/STAT3 signaling pathway in heart tissues, and co-treatment with AG490, a specific JAK2/STAT3 inhibitor, blocked not only the protective effects of BBR, but also the inhibition of BBR on MI/R-induced ER stress. In H9C2 cells, treatment with BBR (50 µmol/L) markedly reduced SIR-induced cell apoptosis, oxidative stress and ER stress, which were abolished by transfection with JAK2 siRNA. CONCLUSION: BBR ameliorates MI/R injury in rats by activating the AK2/STAT3 signaling pathway and attenuating ER stress-induced apoptosis.

Effects of Sevoflurane Inhalation During Cardiopulmonary Bypass on Pediatric Patients: A Randomized Controlled Clinical Trial.

The effects of sevoflurane inhalation during cardiopulmonary bypass (CPB) on postoperative courses and serum cardiac troponin I (cTnI) concentrations in pediatric patients undergoing cardiac surgery have not been extensively investigated. In this single-center, prospective, randomized trial, an anesthetic regimen containing 2% sevoflurane used throughout the CPB process was compared with a total intravenous anesthesia (TIVA) regimen. One hundred and three patients undergoing congenital heart defect repair with CPB were included in this prospective randomized controlled study. They were randomized into two groups: the sevoflurane group, who received 2% sevoflurane during CPB via an oxygenator, and the control group, who received only an oxygen-air mixture. The pre- and intra-operative parameters were comparable between the two groups. There was a slight but significant increase of arterial diastolic pressure in the sevoflurane group immediately after CPB compared with control patients (46.9 ± 9.3 mm Hg vs. 43.6 ± 8.9 mm Hg; p = 0.033). There was no death in either group. The postoperative ventilation time (in mean [95% confidence interval]) was shorter in the sevoflurane group than that in the control group (26.1 [19.2, 33.0] h vs. 37.7 [24.4, 50.9] h; p = 0.014). The postoperative ICU time, hospital days, and serial serum cTnI concentrations were not significantly different between the two groups. Inhalation of 2% sevoflurane during CPB is beneficial to the recovery of pediatric patients undergoing cardiac surgery but has no significant effect on postoperative cTnI release.

Sirtuin Type 1 Mediates the Retinal Protective Effect of Hydrogen-Rich Saline Against Light-Induced Damage in Rats.

PURPOSE: Molecular hydrogen has been used as an antioxidant to treat many diseases in clinical and animal studies. However, the therapeutic mechanism of molecular hydrogen remains unclear. We previously reported mitigation of light-induced damage in the rat retina by intraperitoneal injection of hydrogen-rich saline (HRS). In the present study, we investigated whether Sirtuin Type 1 (Sirt1), a class III histone deacetylase, mediates the retinal protective effect of HRS in rats with light-induced retinal damage. METHODS: Rats were treated with HRS for 5 days after intense light exposure, and then ERGs were performed and retinas were collected to evaluate the effect of HRS on Sirt1 expression. The necessity of Sirt1 for the retinal protective effect of HRS was investigated using the Sirt1 activator resveratrol, the Sirt1 inhibitor EX-527, and short interfering RNAs. RESULTS: In light-damaged retinas, 5 days of HRS treatment increased Sirt1 expression, mitigated a- and b-wave amplitude reduction, and decreased the reduction of outer nuclear cell layers. The Sirt1 activator resveratrol mimicked the effect of HRS in light-damaged retinas. This result supported our hypothesis that Sirt1 mediates the protective effect of HRS. Additionally, the retinal protective effect of HRS was inhibited by both the Sirt1 inhibitor EX-527 and Sirt1 targeted short interfering RNAs. Hydrogen-rich saline also increased B-cell lymphoma 2 (Bcl-2) expression and the activity of the antioxidant enzyme superoxide dismutase (SOD). Conversely, HRS decreased Bcl2-associated X protein expression, cleaved caspase-3, and oxidant-stress product malondialdehyde (MDA) in a Sirt1-dependent manner. CONCLUSIONS: Sirt1 mediates light-induced damage mitigation by HRS through inhibition of apoptosis and oxidant-stress.

The myocardial protective effects of a moderate-potassium blood cardioplegia in pediatric cardiac surgery: a randomized controlled trial.

BACKGROUND: We investigated the myocardial protective effect of a moderate-potassium cold blood cardioplegic solution (K+, 10 mmol/L) in pediatric cardiac surgery. METHODS: Sixty-eight pediatric patients with congenital heart disease and undergoing open heart surgery with cardiopulmonary bypass were randomly allocated to the high potassium (HP [K+, 20 mmol/L, n=31]) cold blood cardioplegia group or the moderate potassium (MP [K+, 10 mmol/L, n=37]) cold blood cardioplegia group. Heart arresting time, rhythm recovery time, mechanical ventilation time, inotropic drug use in the intensive care unit, perioperative serum cardiac troponin I concentrations, morbidities, and mortalities were compared between the two groups. RESULTS: There were no differences in cardiopulmonary bypass time, aorta cross-clamping time, cardioplegia volume, lowest body temperature during cardiopulmonary bypass, total volume of cardioplegia delivered, hematocrit value, and fluid output during the operation between the two groups. However, there was a longer arresting time and a shorter rhythm recovery time in the MP group (35.6±2.4 s, and 30.8±3.1 s) when compared with that in the HP group (24.7±2.7 s, and 42.0±4.0 s, both p<0.05). The total mediastinal drainage volume, the length of stay in the intensive care unit, the postoperative inotropic drug use, and the postoperative hospital time were similar between the two groups, but the number of patients with a long postoperative mechanical ventilation time (>24 hours) in the MP group (6 of 36) was less than that in HP group (13 of 30; p<0.05). At 1 hour, 3 hours, and 6 hours after myocardium reperfusion, the serum concentration of cardiac troponin I significantly decreased in the MP group (in ng/mL: 15.18±3.57, 24.83±4.91, and 19.62±3.93, respectively) when compared with that in the HP group (in ng/mL: 32.67±5.31, 39.26±7.43, and 30.52±5.17, respectively, p<0.05). CONCLUSIONS: The present study demonstrated that the M (10 mmol/L) cold blood cardioplegia formula is associated with better myocardial protective effects when compared with conventional HP cardioplegia in pediatric patients.

The association between OGG1 Ser326Cys polymorphism and lung cancer susceptibility: a meta-analysis of 27 studies.

BACKGROUND: Numerous studies have investigated association of OGG1 Ser326Cys polymorphism with lung cancer susceptibility; however, the findings are inconsistent. Therefore, we performed a meta-analysis based on 27 publications encompass 9663 cases and 11348 controls to comprehensively evaluate such associations. METHODS: We searched publications from MEDLINE and EMBASE which were assessing the associations between OGG1 Ser326Cys polymorphism and lung cancer risk. We calculated pooled odds ratio (OR) and 95% confidence interval (CI) by using either fixed-effects or random-effects model. We used genotype based mRNA expression data from HapMap for SNP rs1052133 in normal cell lines among 270 subjects with four different ethnicities. RESULTS: The results showed that individuals carrying the Cys/Cys genotype did not have significantly increased risk for lung cancer (OR = 1.15, 95% CI = 0.98-1.36) when compared with the Ser/Ser genotype; similarly, no significant association was found in recessive, dominant or heterozygous co-dominant model (Ser/Cys vs. Cys/Cys). However, markedly increased risks were found in relatively large sample size (Ser/Ser vs. Cys/Cys: OR = 1.29, 95% CI = 1.13-1.48, and recessive model: OR = 1.19, 95% CI = 1.07-1.32). As to histological types, we found the Cys/Cys was associated with adenocarcinoma risk (Ser/Ser vs. Cys/Cys: OR = 1.32, 95% CI = 1.12-1.56; Ser/Cys vs. Cys/Cys: OR = 1.19, 95% CI = 1.04-1.37, and recessive model OR = 1.23, 95% CI = 1.08-1.40). No significant difference of OGG1 mRNA expression was found among genotypes between different ethnicities. CONCLUSIONS: Despite some limitations, this meta-analysis established solid statistical evidence for an association between the OGG1 Cys/Cys genotype and lung cancer risk, particularly for studies with large sample size and adenocarcinoma, but this association warrants additional validation in larger and well designed studies.

Calpain inhibitor MDL 28170 protects against the Ca2+ paradox in rat hearts.

The calcium paradox represents an important model in which to study myocardial injuries due to intracellular Ca(2+) overload. In a previous study, calpain was transiently activated in Ca(2+) -paradoxic hearts. The aim of the present study was to determine the role of calpain in myocardial dysfunction in hearts subjected to the Ca(2+) paradox and to elucidate the underlying mechanisms. Rat hearts were isolated, Langendorff perfused and subjected to the Ca(2+) paradox, which was induced by 3 min Ca(2+) depletion followed by 30 min Ca(2+) repletion, in the presence or absence of the calpain inhibitor 10 umol/L MDL 28170. Cardiac function was evaluated. Furthermore, cell death and the degradation of troponin I (TnI) were assessed and calpain activity was determined by measurement of the α-fodrin fragment and confocal image analysis. Upon Ca(2+) repletion, the hearts immediately deteriorated, exhibiting a marked depression in cardiac function and an enlarged myocardial injury area. This was accompanied by significant increases in lactate dehydrogenase, mitochondrial release of cytochrome c, the apoptotic index and degraded TnI. These changes were significantly inhibited by MDL 28170, with the exception of TnI degradation. Compared with the control group, Ca(2+) -paradoxic hearts showed a marked increase in cleaved 150 kDa fragments resulting from specific calpain-mediated proteolysis of α-fodrin. This effect was attenuated by MDL 28170. Confocal image analysis revealed the translocation of both µ- and m-calpain to the sarcolemmal membrane in Ca(2+) -paradoxic hearts, indicating increased activity of both isoforms. The results suggest that the Ca(2+) paradox promotes calpain activity, leading to necrosis, apoptosis and myocardial dysfunction.

The myocardial protective effects of a moderate-potassium adenosine-lidocaine cardioplegia in pediatric cardiac surgery.

OBJECTIVES: We sought to evaluate a moderate-potassium cardioplegic solution using adenosine and lidocaine as the arresting and protecting cardioprotective combination in pediatric cardiac surgery. METHODS: One hundred thirty-four patients with congenital heart disease were randomly allocated to one of 3 groups according to the cardioplegia formula used: the high-potassium (HP) group (K(+), 20 mmol/L), 46 patients; the high-potassium adenosine-lidocaine (HPAL) group (K(+), 20 mmol/L; adenosine, 0.7 mmol/L; and lidocaine, 0.7 mmol/L), 44 patients; and the moderate-potassium adenosine-lidocaine (MPAL) group (K(+), 10 mmol/L; adenosine, 0.7 mmol/L; and lidocaine, 0.7 mmol/L), 44 patients. Hemodynamic data during the operation and postoperative data were recorded. Serum cardiac troponin I concentrations were examined at the time points of before cardiopulmonary bypass and 1, 3, 6, 12, and 24 hours after aortic crossclamp removal. RESULTS: At the end of cardiopulmonary bypass and modified ultrafiltration, the systolic and pulse pressures of the MPAL group were significantly increased compared with the respective values of the HP group. At the time points of 1 to 12 hours after reperfusion, the levels of serum cardiac troponin I were significantly decreased in the MPAL group compared with those in the HP and HPAL groups. CONCLUSIONS: The MPAL cardioplegia formula was associated with better myocardial protective effects.