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.

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.

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.

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.

Nucleoid-phagy: a novel safeguard against mitochondrial DNA-Induced inflammation.

Mitochondria, the powerhouses of the cell, play pivotal roles in cellular processes ranging from energy production to innate immunity. Their unique double-membrane structure typically sequesters mitochondrial DNA (mtDNA) from the rest of the cell. However, under oxidative or immune stress, mtDNA can escape into the cytoplasm, posing a threat as a potential danger signal. The accumulation of cytoplasmic mtDNA can disrupt cellular immune balance and trigger cell death. Our research unveils a novel quality control mechanism, which we term "nucleoid-phagy", that safeguards cellular homeostasis by clearing mislocalized mtDNA. We demonstrate that TFAM, a key protein involved in mtDNA folding and wrapping, accompanies mtDNA into the cytoplasm under stress conditions. Remarkably, TFAM acts as an autophagy receptor, interacting with LC3B to facilitate the autophagic clearance of cytoplasmic mtDNA, thereby preventing the activation of the pro-inflammatory CGAS-STING1 pathway. This study provides unprecedented insights into cytoplasmic mtDNA quality control and offers new perspectives on mitigating inflammatory responses in mitochondrial-related diseases.

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.

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.

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.

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.