Protective Effects of MicroRNA-200b-3p Encapsulated by Mesenchymal Stem Cells-Secreted Extracellular Vesicles in Myocardial Infarction Via Regulating BCL2L11.

Background Extracellular vesicles (EVs) are a popular treatment candidate for myocardial injury. This work investigated the effects of mesenchymal stem cells (MSCs)-secreted EVs-derived miR-200b-3p on cardiomyocyte apoptosis and inflammatory response after myocardial infarction (MI) through targeting BCL2L11 (Bcl-2-like protein 11) . Methods and Results EVs from MSCs were isolated and identified. EVs from MSCs with transfection of miR-200b-3p for overexpression were injected into MI mice. The effect of miR-200b-3p on cardiac function, infarction area, myocardial fibrosis, cardiomyocyte apoptosis, and inflammatory response was determined in MI mice. The targeting relationship between miR-200b-3p and BCL2L11 was verified, and the interaction between BCL2L11 and NLR family pyrin domain containing 1 (NLRP1) was also verified. MI mice were injected with an overexpressing BCL2L11 lentiviral vector to clarify whether BCL2L11 can regulate the effect of miR-200b-3p on MI mice. EVs from MSCs were successfully extracted. MSCs-EVs improved cardiac function and reduced infarction area, apoptosis of cardiomyocytes, myocardial fibrosis, and inflammation in MI mice. Upregulation of miR-200b-3p further enhanced the effects of MSCs-EVs on the myocardial injury of MI mice. BCL2L11 was targeted by miR-200b-3p and bound to NLRP1. Upregulation of BCL2L11 negated the role of miR-200b-3p-modified MSCs-EVs in MI mice. Conclusions A summary was obtained that miR-200b-3p-encapsulated MSCs-EVs protect against MI-induced apoptosis of cardiomyocytes and inflammation via suppressing BCL2L11.

Preoperative albumin corrected anion gap is associated with in-hospital and long-term mortality in patients undergoing coronary artery bypass grafting in a retrospective cohort study.

Background: Coronary artery disease remains a global health concern and the leading cause of death. Till today, coronary artery bypass grafting (CABG) is one of the main treatment strategies for coronary artery disease, especially for Multivessel coronary disease or complex coronary lesions. The present study aimed to explore the relationship of preoperative albumin corrected anion gap (ACAG) with mortality in all those patients who undergoing CABG. Methods: All the patients undergoing CABG were included in the study. All clinical data were collected from CareVue and MetaVision system. The predictive value of ACAG for mortality was determined by receiver operating characteristic (ROC) curves survival curves were estimated using the Kaplan-Meier method. Multivariate regression models were constructed to determine the association of ACAG with mortality. Results: A total of 2,180 patients were identified and divided into a high ACAG group (ACAG ≥16.0 mmol/L) and low ACAG group (ACAG <16.0 mmol/L) according to the ROC analysis. Patients in the high ACAG group were older and presented with more comorbidities and concomitant valvular surgeries. Further more, in the high ACAG group, we observed a higher length of stay in the intensive care unit [3.88 (2.15, 7.09) vs. 2.29 (1.29, 3.94), P<0.001]. Both the in-hospital mortality [28 (4.5%) vs. 11 (0.7%), P<0.001], and the 4-year mortality [125 (27.1%) vs. 111 (12.7%), P<0.001] were also rised in those patients. And it was also showed in the survival curves, patients with ACAG ≥16.0 mmol/L had a significant lower 4-year survival (P<0.001). While in the multivariate regression model, we found ACAG was act as an independent risk factor for both the in-hospital mortality [odds ratio (OR): 1.248 (1.060, 1.470), P=0.008] and the 4-year mortality [hazard ratio (HR): 1.134 (1.063, 1.210), P<0.001]. An ACAG ≥16.0 mmol/L was significantly associated with a 2.7-fold risk of in-hospital mortality [OR: 2.732 (1.129, 6.610), P=0.026]. Conclusions: Preoperative ACAG is an independent risk factor for in-hospital and long-term mortality in CABG patients. A higher ACAG may relate to severe coronary artery stenosis and cardiac dysfunction, which is more likely to lead to a postoperative systemic inflammatory response, microcirculation disorder, and subsequent complications.

ELAVL1 is transcriptionally activated by FOXC1 and promotes ferroptosis in myocardial ischemia/reperfusion injury by regulating autophagy.

AIMS: Myocardial ischemia is the most common form of cardiovascular disease and the leading cause of morbidity and mortality. Understanding the mechanisms is very crucial for the development of effective therapy. Therefore, this study aimed to investigate the functional roles and mechanisms by which ELAVL1 regulates myocardial ischemia and reperfusion (I/R) injury. METHODS: Mouse myocardial I/R model and cultured myocardial cells exposed to hypoxia/reperfusion (H/R) were used in this study. Features of ferroptosis were evidenced by LDH activity, GPx4 activity, cellular iron, ROS, LPO, and GSH levels. The expression levels of autophagy markers (Beclin-1, p62, LC3), ELAVL1 and FOXC1 were measured by qRT-PCR, immunostaining and western blot. RIP assay, biotin-pull down, ChIP and dual luciferase activity assay were employed to examine the interactions of ELAVL1/Beclin-1 mRNA and FOXC1/ELAVL1 promoter. CCK-8 assay was used to examine viability of cells. TTC staining was performed to assess the myocardial I/R injury. RESULTS: Myocardial I/R surgery induced ferroptosis and up-regulated ELAVL1 level. Knockdown of ELAVL1 decreased ferroptosis and ameliorated I/R injury. Si-ELAVL1 repressed autophagy and inhibition of autophagy by inhibitor suppressed ferroptosis and I/R injury in myocardial cells. Increase of autophagy could reverse the effects of ELAVL1 knockdown on ferroptosis and I/R injury. ELAVL1 directly bound with and stabilized Beclin-1 mRNA. Furthermore, FOXC1 bound to ELAVL1 promoter region and activated its transcription upon H/R exposure. CONCLUSION: FOXC1 transcriptionally activated ELAVL1 may promote ferroptosis during myocardial I/R by modulating autophagy, leading to myocardial injury. Inhibition of ELAVL1-mediated autophagic ferroptosis would be a new viewpoint in the treatment of myocardial I/R injury.

Machine perfusion of donor heart with normothermic blood versus hypothermic HTK in preserving coronary endothelium in a porcine model of DCD.

BACKGROUND: Both machine perfusion (MP) of donor hearts with autologous blood and crystalloid perfusates have advantages and disadvantages. Currently, which of the aforementioned preservation strategies can better preserve the coronary endothelium has not yet been determined. We aim to compare the impact of hypothermic continuous MP with histidine-tryptophan-ketoglutarate (HTK) solution versus normothermic continuous MP with autologous blood on coronary endothelium in a porcine ex vivo model of donation following circulatory death (DCD). METHODS: DCD pigs underwent circulatory arrest via asphyxiation followed by 30-minute warm ischemia time. Donor hearts were preserved with either hypothermic MP with HTK solution (MP + HTK group; 4 ℃; n=6), or normothermic MP with blood (MP + blood group; 37 ℃; n=6) for 4 hours. After 2-hour ex vivo reperfusion, the assessment of endothelial-dependent (Edep) and -independent (Eind) relaxation of coronary artery, histopathological analysis, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay were performed. RESULTS: Preservation of DCD hearts with MP + Blood strategy significantly improved both Edep and Eind vasorelaxation of coronary artery compared with MP + HTK strategy (maximum relaxation to bradykinin: MP + HTK 80.9%±2.6% vs. MP + Blood 91.9%±1.9%, P<0.001; maximum relaxation to sodium nitroprusside: MP + HTK 97.1%±1.0% vs. MP + Blood 99.8%±0.2%, P<0.05). MP + Blood strategy significantly decreased nitrotyrosine but increased intercellular adhesion molecule-1 immunoreactivity in the coronary artery. The number of TUNEL-positive cells in MP + Blood group were significantly fewer compared with MP + HTK group. CONCLUSIONS: Compared with MP + HTK strategy, MP + Blood strategy significantly alleviates coronary endothelial dysfunction during donor heart preservation. This protective effect is associated with the inhibition of apoptosis and nitro-oxidative stress in coronary artery.

Meta-Analysis of Repeat Revascularization of Off-Pump and On-Pump Coronary Artery Bypass Surgery.

BACKGROUND: There is an ongoing debate focusing on clinical outcomes after off-pump coronary artery bypass graft surgery (OPCABG) and on-pump coronary artery bypass graft surgery (ONCABG). The objective of the present meta-analysis is to update and compare repeat revascularization rates between OPCABG and ONCABG procedures. METHODS: Data sources including PubMed, EMBASE, Cochrane Library, and ISI Web of Knowledge were searched between 1966 and October 2017. Studies considered for inclusion should conform to the following criteria: prospective randomized clinical trials comparing OPCABG and ONCABG. Outcome should include repeat revascularization rate at the time of 1-month, 1-year, or 5-year follow-up. RESULTS: A literature search yielded 11 randomized controlled trials, and a total of 11,246 patients were randomly allocated to OPCABG or ONCABG procedures. Pooled analysis demonstrated a statistically significant 53% increase in repeat revascularization rate at 1-year follow-up with OPCABG relative to ONCABG in the fixed effects model (odds ratio 1.53, 95% confidence interval: 1.17 to 2.00, p = 0.002), whereas there was no significant difference in repeat revascularization rate at 5-year follow-up between OPCABG and ONCABG in the fixed effects model (OR 1.16, 95% confidence interval: 0.95 to 1.41, p = 0.14). In general, exclusion of any single trial did not affect repeat revascularization rate at 1-year and 5-year follow-up. There was no evidence of significant publication bias. CONCLUSIONS: The result of our meta-analysis suggests that compared with ONCABG, OPCABG increases repeat revascularization rate at 1-year follow-up, but does not affect that of 5-year follow-up.