TFAM is an autophagy receptor that limits inflammation by binding to cytoplasmic mitochondrial DNA.

When cells are stressed, DNA from energy-producing mitochondria can leak out and drive inflammatory immune responses if not cleared. Cells employ a quality control system called autophagy to specifically degrade damaged components. We discovered that mitochondrial transcription factor A (TFAM)-a protein that binds mitochondrial DNA (mtDNA)-helps to eliminate leaked mtDNA by interacting with the autophagy protein LC3 through an autolysosomal pathway (we term this nucleoid-phagy). TFAM contains a molecular zip code called the LC3 interacting region (LIR) motif that enables this binding. Although mutating TFAM's LIR motif did not affect its normal mitochondrial functions, more mtDNA accumulated in the cell cytoplasm, activating inflammatory signalling pathways. Thus, TFAM mediates autophagic removal of leaked mtDNA to restrict inflammation. Identifying this mechanism advances understanding of how cells exploit autophagy machinery to selectively target and degrade inflammatory mtDNA. These findings could inform research on diseases involving mitochondrial damage and inflammation.

Association between admission-blood-glucose-to-albumin ratio and clinical outcomes in patients with ST-elevation myocardial infarction undergoing percutaneous coronary intervention.

Introduction: It is unclear whether admission-blood-glucose-to-albumin ratio (AAR) predicts adverse clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI) who are treated with percutaneous coronary intervention (PCI). Here, we performed a observational study to explore the predictive value of AAR on clinical outcomes. Methods: Patients diagnosed with STEMI who underwent PCI between January 2010 and February 2020 were enrolled in the study. The patients were classified into three groups according to AAR tertile. The primary outcome was in-hospital all-cause mortality, and the secondary outcomes were in-hospital major adverse cardiac events (MACEs), as well as all-cause mortality and MACEs during follow-up. Logistic regression, Kaplan-Meier analysis, and Cox proportional hazard regression were the primary analyses used to estimate outcomes. Results: Among the 3,224 enrolled patients, there were 130 cases of in-hospital all-cause mortality (3.9%) and 181 patients (5.4%) experienced MACEs. After adjustment for covariates, multivariate analysis demonstrated that an increase in AAR was associated with an increased risk of in-hospital all-cause mortality [adjusted odds ratio (OR): 2.72, 95% CI: 1.47-5.03, P = 0.001] and MACEs (adjusted OR: 1.91, 95% CI: 1.18-3.10, P = 0.009), as well as long-term all-cause mortality [adjusted hazard ratio (HR): 1.64, 95% CI: 1.19-2.28, P = 0.003] and MACEs (adjusted HR: 1.58, 95% CI: 1.16-2.14, P = 0.003). Receiver operating characteristic (ROC) curve analysis indicated that AAR was an accurate predictor of in-hospital all-cause mortality (AUC = 0.718, 95% CI: 0.675-0.761) and MACEs (AUC = 0.672, 95% CI: 0.631-0.712). Discussion: AAR is a novel and convenient independent predictor of all-cause mortality and MACEs, both in-hospital and long-term, for STEMI patients receiving PCI.

Exendin-4 alleviates myocardial ischemia reperfusion injury by enhancing autophagy through promoting nuclear translocation of TFEB.

Ischemia-reperfusion (I/R) injury (IRI) is a common clinical consequence of myocardial infarction. Exendin-4 is a glucagon-like peptide-1 (GLP-1) analog that has been demonstrated to alleviate myocardial IRI. Autophagy, a lysosomal pathway balancing cell survival and cell death, is engaged in myocardial IRI. However, whether exendin-4 exerts a protective effect on myocardial IRI by modulating autophagy remains elusive. Herein, we investigated the effect of exendin-4 on autophagic flux and explored the underlying molecular mechanisms. Our data revealed that the autophagic flux was blocked in the human ventricular cardiomyocyte cell lines (AC16) subjected to oxygen glucose deprivation/reoxygenation (OGD/R) in vitro. Exendin-4 pre-treatment markedly restored the blocked autophagic flux induced by OGD/R through promoting nuclear translocation of TFEB and transcription of genes involving autophagy initiation, the effect of which was reversed by TFEB knockdown. The restoration of autophagic flux contributed to multiple beneficial effects of exendin-4 in cardiomyocytes, including reduction of oxidative stress, preservation of mitochondrial network as well as inhibition of cytochrome c leakage from mitochondrial permeability transition pore (MPTP) and the resulting apoptosis. Moreover, the administration of exendin-4 reduced infarct size and preserved cardiac function through its anti-apoptosis and antioxidative effects in vivo. These results shed some light on understanding the novel mechanism of exendin-4 as a protective agent against myocardial IRI.

Prohibitin 1 regulates mtDNA release and downstream inflammatory responses.

Exposure of mitochondrial DNA (mtDNA) to the cytosol activates innate immune responses. But the mechanisms by which mtDNA crosses the inner mitochondrial membrane are unknown. Here, we found that the inner mitochondrial membrane protein prohibitin 1 (PHB1) plays a critical role in mtDNA release by regulating permeability across the mitochondrial inner membrane. Loss of PHB1 results in alterations in mitochondrial integrity and function. PHB1-deficient macrophages, serum from myeloid-specific PHB1 KO (Phb1MyeKO) mice, and peripheral blood mononuclear cells from neonatal sepsis patients show increased interleukin-1ß (IL-1ß) levels. PHB1 KO mice are also intolerant of lipopolysaccharide shock. Phb1-depleted macrophages show increased cytoplasmic release of mtDNA and inflammatory responses. This process is suppressed by cyclosporine A and VBIT-4, which inhibit the mitochondrial permeability transition pore (mPTP) and VDAC oligomerization. Inflammatory stresses downregulate PHB1 expression levels in macrophages. Under normal physiological conditions, the inner mitochondrial membrane proteins, AFG3L2 and SPG7, are tethered to PHB1 to inhibit mPTP opening. Downregulation of PHB1 results in enhanced interaction between AFG3L2 and SPG7, mPTP opening, mtDNA release, and downstream inflammatory responses.

Association of baseline hemoglobin A1c levels with bleeding in patients with non-ST-segment elevation acute coronary syndrome underwent percutaneous coronary intervention: insights of a multicenter cohort study from China.

OBJECTIVE: To investigate the association between baseline hemoglobin A1c (HbA1c) levels and bleeding in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) who underwent percutaneous coronary intervention (PCI). METHODS: This observational cohort study enrolled 6283 consecutive NSTE-ACS patients undergoing PCI from January 1, 2010 to December 31, 2014. Based on baseline HbA1c levels, the patients were divided into the group with HbA1c < 7% ( n = 4740) and the group with HbA1c ≥ 7% (n = 1543). The primary outcomes are major bleeding (BARC grades 3-5) and all-cause death during follow-up. RESULTS: Of patients enrolled, 4705 (74.9%) were male, and 2143 (34.1%) had a history of diabetes mellitus, with a mean (SD) age of 64.13 (10.32) years. The median follow-up duration was 3.21 years. Compared with the patients with HbA1c < 7%, the risk of major bleeding events during follow-up was higher in patients with HbA1c ≥ 7% (adjusted hazard ratio [HR] = 1.57; 95% confidence interval [CI]: 1.01-2.44; P = 0.044), while the risk of all-cause death during follow-up was not associated with the higher HbA1c levels (adjusted HR = 0.88; 95% CI: 0.66-1.18; P = 0.398). CONCLUSIONS: Compared with the lower baseline HbA1c levels, the higher baseline HbA1c levels were associated with an increase in long-term bleeding risk in NSTE-ACS patients undergoing PCI, though higher baseline HbA1c levels were not associated with the higher risk in all-cause death.

Association of Proton Pump Inhibitor and Infection and Major Adverse Clinical Events in Patients With ST-Elevation Myocardial Infarction: A Propensity Score Matching Analysis.

Background: Infections are not common but important in patients with acute myocardial infarction, and are associated with worse outcomes. Infection was proved to be associated with the use of proton pump inhibitor (PPI) in several cohorts. It remains unclear whether PPI usage affects infection in patients with acute myocardial infarction. Methods: We consecutively enrolled patients with ST-elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI) from January 2010 to June 2018. All patients were divided into the PPI group and non-PPI group according to whether the PPI was used. The primary endpoint was the development of infection during hospitalization. Results: A total of 3027 patients were finally enrolled, with a mean age of 62.2 ± 12.6 years. 310 (10.2%) patients were developed infection during hospitalization. Baseline characteristics were similar between the PPI and non-PPI groups (n = 584 for each group) after propensity score analysis. PPI usage was significantly associated with infection based on the propensity score matching analysis (adjusted OR = 1.62, 95% CI = 1.02-2.57, P = 0.041). Comparing to patients with non-PPI usage, PPI administration was positively associated with higher risk of in-hospital all-cause mortality (adjusted OR = 3.25, 95% CI = 1.06-9.97, P = 0.039) and in-hospital major adverse clinical events (adjusted OR = 3.71, 95% CI = 1.61-8.56, P = 0.002). Subgroup analysis demonstrated that the impact of PPI on infection was not significantly different among patients with or without diabetes and patients with age ≥65 years or age <65 years. Conclusion: PPI usage was related to a higher incidence of infection during hospitalization, in-hospital all-cause mortality, and in-hospital major adverse clinical events (MACE) in STEMI patients.

Risk Estimation for Infection in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Percutaneous Coronary Intervention: Development and Validation of a Predictive Score.

Background: Infection during hospitalization is a serious complication among patients who suffered from acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI); however, there are no suitable and accurate means to assess risk. This study aimed to develop and validate a simple scoring system to predict post-AMI infection in such patients. Methods: All patients with ST-segment elevation myocardial infarction (STEMI) undergoing PCI consecutively enrolled from January 2010 to May 2016 were served as derivation cohort, and those from June 2016 to May 2018 as validation cohort, respectively. The primary endpoint was post-AMI infection during hospitalization, and all-cause death and major adverse cardiovascular events (MACE) were considered as secondary endpoints. The simplified risk model was established using logistic regression. The area under the receiver operating curve and calibration of predicted and observed infection risk were calculated. Results: A 24-point risk score was developed, with infection risk ranging from 0.7 to 99.6% for patients with the lowest and highest score. Seven variables including age, Killip classification, insulin use, white blood cell count, serum albumin, diuretic use, and transfemoral approach were included. This model achieved the same high discrimination in the development and validation cohort (C-statistic:0.851) and revealed adequate calibration in both datasets. The incidences of post-AMI infection increased steadily across risk score groups in both development (1.3, 5.1, 26.3, and 69.1%; P < 0.001) and validation (1.8, 5.9, 27.2, and 79.2%; P < 0.001) cohort. Moreover, the risk score demonstrated good performance for infection, in-hospital all-cause death, and MACE among these patients, as well as in patients with the non-ST-elevation acute coronary syndrome. Conclusion: This present risk score established a simple bedside tool to estimate the risk of developing infection and other in-hospital outcomes in patients with STEMI undergoing PCI. Clinicians can use this risk score to evaluate the infection risk and subsequently make evidence-based decisions.

CCAAT/Enhancer-Binding Protein Alpha Is a Novel Regulator of Vascular Smooth Muscle Cell Osteochondrogenic Transition and Vascular Calcification.

Aims: Vascular calcification is a common clinical complication of chronic kidney disease (CKD), atherosclerosis (AS), and diabetes, which is associated with increased cardiovascular morbidity and mortality in patients. The transdifferentiation of vascular smooth muscle cells (VSMCs) to an osteochondrogenic phenotype is a crucial step during vascular calcification. The transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα) plays an important role in regulating cell proliferation and differentiation, but whether it regulates the calcification of arteries and VSMCs remains unclear. Therefore, this study aims to understand the role of C/EBPα in the regulation of vascular calcification. Methods and Results: Both mRNA and protein expression levels of C/EBPα were significantly increased in calcified arteries from mice treated with a high dose of vitamin D3 (vD3). Upregulation of C/EBPα was also observed in the high phosphate- and calcium-induced VSMC calcification process. The siRNA-mediated knockdown of C/EBPα significantly attenuated VSMC calcification in vitro. Moreover, C/EBPα depletion in VSMCs significantly reduced the mRNA expression of the osteochondrogenic genes, e.g., sex-determining region Y-box 9 (Sox9). C/EBPα overexpression can induce SOX9 overexpression. Similar changes in the protein expression of SOX9 were also observed in VSMCs after C/EBPα depletion or overexpression. In addition, silencing of Sox9 expression significantly inhibited the phosphate- and calcium-induced VSMC calcification in vitro. Conclusion: Findings in this study indicate that C/EBPα is a key regulator of the osteochondrogenic transdifferentiation of VSMCs and vascular calcification, which may represent a novel therapeutic target for vascular calcification.

Dual Function of a in vivo Albumin-Labeling Tracer for Assessment of Blood Perfusion and Vascular Permeability in Peripheral Arterial Disease by PET.

BACKGROUND: Peripheral arterial disease (PAD) leads to tissue ischemia in the extremities. Enhanced vascular permeability plays a critical role in targeted delivery of drugs for effective therapeutic angiogenesis and resultant blood perfusion recovery. However, optimal tracers for evaluating this process in PAD patients are lacking. At this time, we employed a novel in vivo albumin-labeling tracer of dual function, termed as 18F-NEB, to assess blood perfusion as well as vascular permeability by positron emission tomography (PET). METHODS AND RESULTS: After successful establishment of mouse hindlimb ischemia (HI) model, static PET imaging was performed 15 min and 2 h post injection (p.i.) of 18F-NEB at 1, 3, 5, 7, 10 and 14 days post-surgery respectively. Gradual recovery of blood supply was detected by PET scan 15 min p.i. and collaborated by serial Laser Doppler. In addition, the highest vascular permeability observed by high local uptake of 18F-NEB at 2 h p.i. was consistent with histological examinations. Furthermore, we quantitatively evaluated the effect of vascular endothelial growth factor (VEGF) stimulus on vascular permeability and blood perfusion by PET scan using 18F-NEB probe in HI model, which were also confirmed by immunohistological results. CONCLUSION: The application of 18F-NEB probe alone by PET can successfully achieve dual imaging of blood perfusion as well as vascular permeability at different time points p.i. and monitor their responses to therapy in PAD model. The simple labeling approach and multipurpose feature suggest the great promise of using this imaging probe in theranostic applications for treating ischemic disease.

The monocyte to high-density lipoprotein cholesterol ratio and outcomes in type 2 diabetes mellitus patients with non-ST-segment elevation acute coronary syndrome.

BACKGROUND: The monocyte to high-density lipoprotein cholesterol ratio (MHR) has been demonstrated as a new marker of inflammation. However, at present, the prognostic value of MHR in type 2 diabetes mellitus (T2DM) accompanied with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) undergoing percutaneous coronary intervention (PCI) is unclear. METHODS: T2DM patients with NSTE-ACS undergoing PCI were consecutively enrolled from January 1, 2010 to December 31, 2014 and divided according to MHR value tertiles. Baseline, procedural, and follow-up data were collected. The primary outcomes were in-hospital major adverse clinical events (MACE). The prespecified secondary outcomes included any bleeding [as indicated by Bleeding Academic Research Consortium definition (BARC) grades 1-5] and death during follow-up. RESULTS: Of the 1,405 enrolled patients, the rates of in-hospital MACE (0.2%, 0.2%, and 1.3%, P=0.043) and bleeding (12.4%, 12.2%, and 17.1%, P=0.048) increased significantly in high MHR tertiles. After 1 year of follow-up, the rates of bleeding (15.0%, 14.5%, and 22.2%, P=0.002) and all-cause death (1.5%, 1.7%, and 4.3%, P=0.010) were higher in higher MHR tertiles. Our results also suggested that MHR was an independent predictor of in-hospital MACE [adjusted odds ratio =8.36; 95% confidence interval (CI): 1.57-44.47; P=0.013] and long-term bleeding (adjusted hazard ratio =1.21; 95% CI: 1.07-1.37; P=0.002). Receiver-operating characteristic curve analysis indicated that MHR >0.022 had a sensitivity of 75.0% and specificity of 72.7% for predicting in-hospital MACE [area under the curve (AUC) =0.722; 95% CI: 0.51-0.933; P=0.040]. Furthermore, Kaplan-Meier curves showed that a higher risk of all-cause death in long-term follow-up was prevalent in patients with high MHR (P=0.033). CONCLUSIONS: The increased level of MHR was related to in-hospital MACE and long-term bleeding events in T2DM patients with NSTE-ACS undergoing PCI.

Association of Parenteral Anticoagulation Therapy With Outcomes in Non-ST-Segment Elevation Acute Coronary Syndrome Patients Without Invasive Therapy: Findings from the Improving Care for Cardiovascular Disease in China (CCC) project.

Our previous study showed that parenteral anticoagulation therapy (PACT) in the context of aggressive antiplatelet therapy failed to improve clinical outcomes in patients undergoing percutaneous coronary intervention for non-ST-segment elevation acute coronary syndrome (NSTE-ACS). However, the role of PACT in patients managed medically remains unknown. This observational cohort study enrolled patients with NSTE-ACS receiving medical therapy from November 2014 to June 2017 in the Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome project. Eligible patients were included in the PACT group and non-PACT group. The primary outcomes were in-hospital all-cause mortality and major bleeding. The secondary outcome included minor bleeding. Among 23,726 patients, 8,845 eligible patients who received medical therapy were enrolled. After adjusting the potential confounders, PACT was not associated with a lower risk of in-hospital all-cause mortality (adjusted odds ratio (OR), 1.25; 95% confidence interval (CI), 0.92-1.71; P = 0.151). Additionally, PACT did not increase the incidence of major bleeding or minor bleeding (major bleeding: adjusted OR, 1.04; 95% CI, 0.80-1.35; P = 0.763; minor bleeding: adjusted OR, 1.27; 95% CI, 0.91-1.75; P = 0.156). The propensity score analysis confirmed the primary analyses. In patients with NSTE-ACS receiving antiplatelet therapy, PACT was not associated with a lower risk of in-hospital all-cause mortality or a higher bleeding risk in patients with NSTE-ACS receiving non-invasive therapies and concurrent antiplatelet strategies. Randomized clinical trials are warranted to reevaluate the safety and efficacy of PACT in all patients with NSTE-ACS who receive noninvasive therapies and current antithrombotic strategies.

Development and Validation of a Risk Score for Predicting Post-acute Myocardial Infarction Infection in Patients Undergoing Percutaneous Coronary Intervention: Study Protocol for an Observational Study.

Background: Post-acute myocardial infarction (post-AMI) infection is an infrequent but important and serious complication in patients with ST-segment elevation myocardial infarction (STEMI) treated with percutaneous coronary intervention (PCI). Predicting its occurrence is essential for future prevention. However, little is known about the prediction of post-AMI infection in such patients to date. This study aims to develop and validate a new risk score based on risk factors for early prediction of infection in STEMI patients undergoing PCI. Methods: This prospective, multi-center and observational study assesses the predictive value of risk score for post-AMI infection among a cohort of patients hospitalized due to STEMI. The STEMI patients undergoing PCI enrolled between January 1st 2010 and May 31st 2016 were served as a development cohort while those enrolled from June 1st 2016 to May 31st 2018 were served as validation cohort. The primary endpoint was post-AMI infection during hospitalization, defined as infection requiring antibiotics (reflecting the clinical influence of infection compatible with the necessity for additional treatment), and all-cause death and major adverse cardiovascular events (MACE) including all-cause death, recurrent myocardial infarction, target vessel revascularization, and stroke were considered as secondary endpoints. The risk score model based on risk factors was established using stepwise logistic regression, and will be validated in other centers and external patients with non-ST-elevation acute coronary syndrome (NSTE-ACS). Results: This study will provide evidence on prognostic property, reliability of scoring, comparative performance, and suitability of the novel model for screening purpose in order to be recommended for clinical practice. Discussion: Our study is designed to develop and validate a clinical risk score for predicting infection in participants with STEMI who have undergone PCI. This simple tool may therefore improve evaluation of post-AMI infection and enhance future researches into the best practices to prevent or reduce infection in such patients. Clinical Trial Registration: www.chictr.org.cn, identifier: ChiCTR1900028278.

The Release of Peripheral Immune Inflammatory Cytokines Promote an Inflammatory Cascade in PCOS Patients via Altering the Follicular Microenvironment.

Background: Hormones and immune imbalance are critical factors in polycystic ovary syndrome (PCOS). The alternation of immune microenvironment of oocytes may play a significant role in infertility of PCOS patients. Objective: This study explores the role of follicular fluid microenvironment change in inflammatory pathways activation of granulosa cells (GCs) in PCOS women infertility. Methods: We enrolled 27 PCOS patients and 30 controls aged 22 to 38 years who underwent IVF and collected their luteinized granulosa cells (LGCs). Meanwhile, a granulosa-like tumor cell line (KGN) as a cell-model assisted this study. Key inflammatory markers in human ovarian GCs and follicular fluid were detected by RT-qPCR, Western blotting, or ELISA. The KGN cells were treated with follicle supernatant mixed with normal medium to simulate the microenvironment of GCs in PCOS patients, and the inflammation indicators were observed. The assembly of NLRP3 inflammasomes was detected by immunofluorescence techniques. Dihydroethidium assay and EdU proliferation assay were used to detect ROS and cell proliferation by flow cytometry. Results: Compared with normal controls (n = 19), IL-1ß (P = 0.0005) and IL-18 (P = 0.021) in the follicular fluid of PCOS patients (n = 20) were significantly increased. The NF-κB pathway was activated, and NLRP3 inflammasome was formatted in ovarian GCs of PCOS patients. We also found that inflammation of KGN cells was activated with LPS irritation or stimulated by follicular fluid from PCOS patients. Finally, we found that intracellular inflammation process damaged mitochondrial structure and function, which induced oxidative stress, affected cellular metabolism, and impaired cell proliferation. Conclusion: Inflammatory microenvironment alteration in the follicular fluid of PCOS patients leads to activated inflammatory pathway in GCs, serving as a crucial factor that causes adverse symptoms in patients. This study provides a novel mechanism in the inflammatory process of PCOS.

The association of baseline N-terminal pro-B-type natriuretic peptide with short and long-term prognosis following percutaneous coronary intervention in non-ST segment elevation acute coronary syndrome with multivessel coronary artery disease: a retrospective cohort study.

BACKGROUND: Several studies have shown that N-terminal pro-B-type natriuretic peptide (NT-proBNP) is strongly correlated with the complexity of coronary artery disease and the prognosis of patients with non-ST segment elevation acute coronary syndrome (NSTE-ACS), However, it remains unclear about the prognostic value of NT-proBNP in patients with NSTE-ACS and multivessel coronary artery disease (MCAD) undergoing percutaneous coronary intervention (PCI). Therefore, this study aimed to reveal the relationship between NT-proBNP levels and the prognosis for NSTE-ACS patients with MCAD undergoing successful PCI. METHODS: This study enrolled 1022 consecutive NSTE-ACS patients with MCAD from January 2010 to December 2014. The information of NT-proBNP levels was available from these patients. The primary outcome was in-hospital all-cause death. In addition, the 3-year follow-up all-cause death was also ascertained. RESULTS: A total of 12 (1.2%) deaths were reported during hospitalization. The 4th quartile group of NT-proBNP (> 1287 pg/ml) showed the highest in-hospital all-cause death rate (4.3%) (P < 0.001). Besides, logistic analyses revealed that the increasing NT-proBNP level was robustly associated with an increased risk of in-hospital all-cause death (adjusted odds ratio (OR): 2.86, 95% confidence interval (CI) = 1.16-7.03, P = 0.022). NT-proBNP was able to predict the in-hospital all-cause death (area under the curve (AUC) = 0.888, 95% CI = 0.834-0.941, P < 0.001; cutoff: 1568 pg/ml). Moreover, as revealed by cumulative event analyses, a higher NT-proBNP level was significantly related to a higher long-term all-cause death rate compared with a lower NT-proBNP level (P < 0.0001). CONCLUSIONS: The increasing NT-proBNP level is significantly associated with the increased risks of in-hospital and long-term all-cause deaths among NSTE-ACS patients with MCAD undergoing PCI. Typically, NT-proBN P > 1568 pg/ml is related to the all-cause and in-hospital deaths.

The AMPK-MFN2 axis regulates MAM dynamics and autophagy induced by energy stresses.

Energy deprivation activates the cellular energy sensor AMP-activated protein kinase (AMPK), which in turn induces macroautophagy/autophagy. The mitochondrial-associated ER membrane (MAM) plays a key role in mitochondrial division and autophagy, and the mitochondrial fusion protein MFN2 (mitofusin 2) tethers the MAM, but the mechanism by which AMPK and MFN2 regulate autophagy in response to energy stress remains unclear. Here, we found that energy stress not only triggers mitochondrial fission and autophagy, but more importantly increases the number of MAMs, a process that requires AMPK. Interestingly, under energy stress, considerable amounts of AMPK translocate from cytosol to the MAM and the mitochondrion as mitochondrial fission occurs. Unexpectedly, AMPK interacts directly with MFN2. The autophagic ability of mouse embryonic fibroblasts (MEFs) lacking MFN2 (mfn2-/-) is significantly attenuated in response to energy stress as compared to wild-type MEFs (WT MEFs), while re-expression of MFN2 in mfn2-/- cells rescues the autophagy defects of these cells. The abundance of MAMs is also greatly reduced in MFN2-deficient cells. Functional experiments show that the oxygen consumption rate and the glycolytic function of cells lacking MFN2 but not MFN1 are obviously attenuated, and MFN2 is important for cell survival under energy stress. In conclusion, our study establishes the molecular link between the energy sensor AMPK and the MAM tether MFN2, and reveals the important role of AMPK and MFN2 in energy stress-induced autophagy and MAM dynamics.Abbreviations: ACTB, actin beta; AMPK, AMP-activated protein kinase; BECN1, beclin 1; CANX, calnexin; ER, endoplasmic reticulum; HRP, horseradish peroxidase; EM, electron microscopy; FL, full-length; KD, kinase dead, KO, knockout; MAb, monoclonal antibody; MAMs, mitochondria-associated membranes; MAP1LC3/LC3B, microtubule associated protein 1 light chain 3; MFN2, mitofusin 2; OPA1, OPA1 mitochondrial dynamin like GTPase; PAb, polyclonal antibody; PtdIns3K, class III phosphatidylinositol 3-kinase; PtdIns3P, phosphatidylinositol 3-phosphate; SD, standard deviation; TEM, transmission electron microscopy; TOMM20, translocase of outer mitochondrial membrane 20; ULK1, unc-51 like autophagy activating kinase 1; MEF, mouse embryonic fibroblast; WT, wildtype.

Using Flame-Assisted Printing to Fabricate Large Nanostructured Oxide Thin Film for Electrochromic Applications.

Flame spray pyrolysis was a process to produce oxide nanoparticles in a self-sustaining flame. When the produced nanoparticles were deposited on a substrate, nanostructured oxide thin films could be obtained. However, the size of the thin film was usually limited by the fixed substrate. Here, we demonstrated that thin film with a large area could be deposited by using the moving substrate, which was precisely controlled by servo motors. As a result, the flame tip could scan over the substrate and deposit the nanoparticles on it line by line, analogues to a printing process called flame-assisted printing (FAP). As an example, nanostructured bismuth-oxide thin films with a size of up to 20 cm × 20 cm were deposited with the FAP process. The bismuth-oxide thin film exhibited a stable electrochromic property with a high modulation of 70.5%. The excellent performance could be ascribed to its porous nanostructure formed in the FAP process. The process can be extended to deposit other various oxides (e.g., tungsten-oxide) thin films with a large size for versatile applications.

Mitochondrial Contact Sites in Inflammation-Induced Cardiovascular Disease.

The mitochondrion, the ATP-producing center, is both physically and functionally associated with almost all other organelles in the cell. Mitochondrial-associated membranes (MAMs) are involved in a variety of biological processes, such as lipid exchange, protein transport, mitochondrial fission, mitophagy, and inflammation. Several inflammation-related diseases in the cardiovascular system involve several intracellular events including mitochondrial dysfunction as well as disruption of MAMs. Therefore, an in-depth exploration of the function of MAMs will be of great significance for us to understand the initiation, progression, and clinical complications of cardiovascular disease (CVD). In this review, we summarize the recent advances in our knowledge of MAM regulation and function in CVD-related cells. We discuss the potential roles of MAMs in activating inflammation to influence the development of CVD.

Association of in-hospital intensive statins dosage and death in arteriosclerotic cardiovascular disease with percutaneous coronary intervention: insights of multicentre cohort from China.

PURPOSE: In-hospital statin dosage-related effect remains unknown for patients with arteriosclerotic cardiovascular disease (ASCVD). This study aimed to determine the associations of different in-hospital intensive statins dosages with the prognosis for patients in the era of percutaneous coronary intervention (PCI). METHODS: From January 2010 to December 2014, consecutive ASCVD patients receiving PCI were enrolled from five centres in China. All the enrolled patients were classified into high-dose (40 mg atorvastatin or 20 mg rosuvastatin) or low-dose (20 mg atorvastatin or 10 mg rosuvastatin) intensive statin group. In-hospital all-cause death was the primary outcome. RESULTS: Of the 7008 patients included in this study, 5248 received low-dose intensive statins (mean age, 64.28 ± 10.39; female, 25.2%), whereas 1760 received high-dose intensive statins (mean age, 63.68 ± 10.59; female, 23.1%). There was no significant difference in the in-hospital all-cause death between the two groups (adjusted OR, 1.27; 95% CI, 0.43-3.72; P = 0.665). All-cause death was similar between the two groups during the 30-day follow-up period (adjusted HR, 1.28; 95% CI, 0.55-2.97; P = 0.571). However, the high-dose intensive statins were tightly associated with the reduction in in-hospital dialysis (adjusted OR, 0.11; 95% CI, 0.01-0.81; P = 0.030). Besides, primary analyses were confirmed by subgroup analyses. CONCLUSIONS: The in-hospital high-dose intensive statins are not associated with the lower risk of in-hospital or 30-day all-cause death among ASCVD patients undergoing PCI. Given the robust beneficial effect of high-dose intensive statins with in-hospital dialysis, an individualized high-dose intensive statin therapy can be rational in specified populations.

Mitochondrial Quality Control in Cardiomyocytes: A Critical Role in the Progression of Cardiovascular Diseases.

Mitochondria serve as an energy plant and participate in a variety of signaling pathways to regulate cellular metabolism, survival and immunity. Mitochondrial dysfunction, in particular in cardiomyocytes, is associated with the development and progression of cardiovascular disease, resulting in heart failure, cardiomyopathy, and cardiac ischemia/reperfusion injury. Therefore, mitochondrial quality control processes, including post-translational modifications of mitochondrial proteins, mitochondrial dynamics, mitophagy, and formation of mitochondrial-driven vesicles, play a critical role in maintenance of mitochondrial and even cellular homeostasis in physiological or pathological conditions. Accumulating evidence suggests that mitochondrial quality control in cardiomyocytes is able to improve cardiac function, rescue dying cardiomyocytes, and prevent the deterioration of cardiovascular disease upon external environmental stress. In this review, we discuss recent progress in understanding mitochondrial quality control in cardiomyocytes. We also evaluate potential targets to prevent or treat cardiovascular diseases, and highlight future research directions which will help uncover additional mechanisms underlying mitochondrial homeostasis in cardiomyocytes.

Validation and Comparison of Six Risk Scores for Infection in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Percutaneous Coronary Intervention.

Aims: Very few of the risk scores to predict infection in ST-segment elevation myocardial infarction (STEMI) patients undergoing percutaneous coronary intervention (PCI) have been validated, and reports on their differences. We aimed to validate and compare the discriminatory value of different risk scores for infection. Methods: A total of 2,260 eligible patients with STEMI undergoing PCI from January 2010 to May 2018 were enrolled. Six risk scores were investigated: age, serum creatinine, or glomerular filtration rate, and ejection fraction (ACEF or AGEF) score; Canada Acute Coronary Syndrome (CACS) risk score; CHADS2 score; Global Registry for Acute Coronary Events (GRACE) score; and Mehran score conceived for contrast induced nephropathy. The primary endpoint was infection during hospitalization. Results: Except CHADS2 score (AUC, 0.682; 95%CI, 0.652-0.712), the other risk scores showed good discrimination for predicting infection. All risk scores but CACS risk score (calibration slope, 0.77; 95%CI, 0.18-1.35) showed best calibration for infection. The risks scores also showed good discrimination for in-hospital major adverse clinical events (MACE) (AUC range, 0.700-0.786), except for CHADS2 score. All six risk scores showed best calibration for in-hospital MACE. Subgroup analysis demonstrated similar results. Conclusions: The ACEF, AGEF, CACS, GRACE, and Mehran scores showed a good discrimination and calibration for predicting infection and MACE.