Where the cerebral infarction meets child, be vigilant about patent foramen ovale: a case report.

Background: While cerebral infarction in children is rare, its prognosis is poor, and this condition can seriously burden society and families. A correlation between patent foramen ovale (PFO) and ischemic stroke has not been found in pediatric patients. Case presentation: We report a 7-year-old boy who suffered from multiple cerebral infarctions. Subsequently, the patient was diagnosed with an abnormal shunt of PFO. He underwent PFO closure and was followed up for 1 year. The patient did not experience any further cerebral infarction. Conclusions: With this case report, we want to illustrate that although the incidence rate of ischemic cerebral infarction in adolescents is very low, we should not neglect the role of PFO. Therefore, after exclusion other causes of cerebral infarction, PFO should be considered in adolescent and adult stroke patients with adult closure criteria in the same way.

Role of C/EBP Homologous Protein in Vascular Stenosis After Carotid Artery Injury.

The study aims to explore the fluctuating expression of C/EBP Homologous Protein (CHOP) following rat carotid artery injury and its central role in vascular stenosis. Using in vivo rat carotid artery injury models and in vitro ischemia and hypoxia cell models employing human aortic endothelial cells (HAECs) and vascular smooth muscle cells (T/G HA-VSMCs), a comprehensive investigative framework was established. Histological analysis confirmed intimal hyperplasia in rat models. CHOP expression in vascular tissues was assessed using Western blot and immunohistochemical staining, and its presence in HAECs and T/G HA-VSMCs was determined through RT-PCR and Western blot. The study evaluated HAEC apoptosis, inflammatory cytokine secretion, cell proliferation, and T/G HA-VSMCs migration through Western blot, ELISA, CCK8, and Transwell migration assays. The rat carotid artery injury model revealed substantial fibrous plaque formation and vascular stenosis, resulting in an increased intimal area and plaque-to-lumen area ratio. Notably, CHOP is markedly elevated in vessels of the carotid artery injury model compared to normal vessels. Atorvastatin effectively mitigated vascular stenosis and suppresses CHOP protein expression. In HAECs, ischemia and hypoxia-induced CHOP upregulation, along with heightened TNFα, IL-6, caspase3, and caspase8 levels, while reducing cell proliferation. Atorvastatin demonstrated a dose-dependent suppression of CHOP expression in HAECs. Downregulation of CHOP or atorvastatin treatment led to reduced IL-6 and TNFα secretion, coupled with augmented cell proliferation. Similarly, ischemia and hypoxia conditions increased CHOP expression in T/G HA-VSMCs, which was concentration-dependently inhibited by atorvastatin. Furthermore, significantly increased MMP-9 and MMP-2 concentrations in the cell culture supernatant correlated with enhanced T/G HA-VSMCs migration. However, interventions targeting CHOP downregulation and atorvastatin usage curtailed MMP-9 and MMP-2 secretion and suppressed cell migration. In conclusion, CHOP plays a crucial role in endothelial injury, proliferation, and VSMCs migration during carotid artery injury, serving as a pivotal regulator in post-injury fibrous plaque formation and vascular remodeling. Statins emerge as protectors of endothelial cells, restraining VSMCs migration by modulating CHOP expression.

cFLIPL Alleviates Myocardial Ischemia-Reperfusion Injury by Inhibiting Endoplasmic Reticulum Stress.

PURPOSE: Endoplasmic reticulum stress (ERS) plays a crucial role in myocardial ischemia-reperfusion injury (MIRI). Cellular FLICE-inhibitory protein (cFLIP) is an essential regulator of apoptosis and plays a major role in regulating ERS. The present study aimed to investigate the effects of long isoform cFLIP (cFLIPL) on endogenous apoptosis and the mechanism of ERS in MIRI. METHODS: The cFLIPL recombinant adenovirus vector was used to infect H9c2 cells and Sprague-Dawley (SD) rats. After infection for 72 h, ischemia was induced for 30 min, and reperfusion was then performed for 2 h to establish the MIRI model in SD rats. H9c2 cells were hypoxic for 4 h and then reoxygenated for 12 h to simulate ischemia/reperfusion (I/R) injury. Model parameters were evaluated by assessing cardiomyocyte viability, cell death (apoptosis), and ERS-related protein expression. In addition, tunicamycin (TM), an ERS agonist, was also added to the medium for pretreatment. Coimmunoprecipitation (Co-IP) of cFLIPL and p38 MAPK protein was performed. RESULTS: cFLIPL expression was decreased in I/R injury and hypoxia/reoxygenation (H/R) injury, and cFLIPL overexpression reduced myocardial infarction in vivo and increased the viability of H9c2 cells in vitro. I/R and H/R upregulated the protein expression of GRP78, IRE-1, and PERK to induce ERS and apoptosis. Interestingly, overexpression of cFLIPL significantly inhibited ERS and subsequent apoptosis, which was reversed by an agonist of ERS. Moreover, Co-IP showed that cFLIPL attenuated ERS and was associated with inhibiting the activation of p38 protein. CONCLUSION: The expression of cFLIPL is significantly downregulated in MIRI, and it is accompanied by excessive ERS and apoptosis. Upregulated cFLIPL suppresses ERS to reduce myocardial apoptosis, which is associated with inhibiting the activity of p38 MAPK. Therefore, cFLIPL may be a potential intervention target for MIRI.

New progress in diagnosis and treatment of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease. Although great progress has been made in its diagnosis and treatment in recent years, its mortality rate is still very significant. The pathophysiology and pathogenesis of PAH are complex and involve endothelial dysfunction, chronic inflammation, smooth muscle cell proliferation, pulmonary arteriole occlusion, antiapoptosis and pulmonary vascular remodeling. These factors will accelerate the progression of the disease, leading to poor prognosis. Therefore, accurate etiological diagnosis, treatment and prognosis judgment are particularly important. Here, we systematically review the pathophysiology, diagnosis, genetics, prognosis and treatment of PAH.

Analysis of cardiovascular disease factors on SARS-CoV-2 infection severity.

Background: At present, COVID-19 is a global pandemic and is seriously harmful to humans. In this retrospective study, the aim was to investigate the interaction between CVD and COVID-19. Methods: A total of 180 patients diagnosed with COVID-19 in Yichang Central People's Hospital from 29 January to 17 March 2020 were initially included. The medical history, clinical manifestations at the time of admission, laboratory test results, hospitalization time and complications were recorded. According to the medical history, the patients were assigned to the nonsevere group with non-CVD (n = 90), the nonsevere group with CVD (n = 22), the severe group with non-CVD (n = 40) and the severe group with CVD (n = 28). Results: In the severe group, compared with non-CVD patients, CVD patients had a significantly higher incidence of fever (P < 0.05). However, compared with the nonsevere group, the severe group had significantly higher proportions of patients with hypertension, type 2 diabetes mellitus, CHD and HF (all P < 0.05). Among the patients with nonsevere COVID-19, the WBC count and the levels of IL-6, CRP, D-dimer, NT-proBNP, and FBG were significantly higher and the Hb level was significantly lower in the CVD patients than in the non-CVD patients (all P < 0.05). However, among the patients with severe COVID-19, only the level of NT-proBNP was significantly higher in CVD patients than in non-CVD patients (P < 0.05). In addition, the WBC count and the levels of IL-6, CRP, D-dimer, CKMB, ALT, AST, SCR, NT-proBNP, and FBG were significantly higher and the Hb level was significantly lower in the severe group than in the nonsevere group (all P < 0.05). However, among the patients with severe COVID-19, the incidences of acute myocardial injury, acute kidney injury, arrhythmia, and sudden death were significantly higher in the CVD group than in the non-CVD group (all P < 0.05). The same results were found in the comparison of the nonsevere group with the severe group. Among the patients with nonsevere COVID-19, those without CVD had a mean hospitalization duration of 25.25 (SD 7.61) days, while those with CVD had a mean hospitalization duration of 28.77 (SD 6.11) days; the difference was significant (P < 0.05). The same results were found in the comparison of the severe group. Conclusions: CVD affects the severity of COVID-19. COVID-19 also increases the risk of severe CVD.

Antecedentes: La infección por SARS-CoV-2 está provocando graves consecuencias en la humanidad. El objetivo de este estudio retrospectivo fue investigar el impacto de las enfermedades cardiovasculares (ECV) en la gravedad de dicha infección. Métodos: Entre el 29 de enero y el 17 de marzo de 2020, se diagnosticaron 180 pacientes con neumonía por SARS-CoV-2 en el Hospital Popular Central de Yichang. Se registraron los antecedentes, manifestaciones clínicas, resultados de laboratorio, tiempo de hospitalización y complicaciones. Los pacientes se dividieron en cuatro grupos: 1) infección no grave sin ECV (n = 90), 2) infección no grave con ECV (n = 22), 3) infección grave sin ECV (n = 40) y 4) infección grave con ECV (n = 28). Resultados: La prevalencia de fiebre en los pacientes con ECV fue significativamente mayor que en aquellos sin ECV (P < 0,05). Sin embargo, en comparación con los pacientes no graves, la proporción de pacientes con hipertensión, diabetes mellitus tipo 2, cardiopatía coronaria e insuficiencia cardíaca en los pacientes graves fue significativamente mayor (p< 0,05). Los niveles de recuento de leucocitos, IL-6, PCR, dímero D, NT-proBNP y glucemia en ayunas (GA) en pacientes con ECV fueron significativamente mayores que en los de pacientes sin ECV, aunque los niveles de Hb fueron significativamente menores que los de los pacientes sin ECV (p< 0,05). Sin embargo, los valores de NT-proBNP en pacientes con ECV fueron significativamente mayores que en los pacientes sin ECV (P< 0,05). Además, el recuento de leucocitos y los niveles de IL-6, PCR, dímero D, CK-MB, ALT, AST, creatinina, NT-proBNPy GA en el grupo de pacientes graves fueron significativamente mayores que en el grupo no grave, mientras que los valores de Hb fueron significativamente menores que en el grupo no grave (p< 0,05). La prevalencia de lesión miocárdica aguda, lesión renal aguda, arritmia y muerte súbita en el grupo con ECV fue significativamente mayor que en el grupo sin ECV (p< 0,05). Los mismos resultados se encontraron al comparar los pacientes no graves con aquellos con infección grave. Entre los pacientes no graves, la duración media de la estancia hospitalaria fue de 25,25 (DE: 7,61) días en los pacientes sin ECV, mientras que la duración media de la estancia hospitalaria fue de 28,77 (DE: 6,11) días en los pacientes con ECV (p< 0,05). Los mismos resultados se observaron al comparar los dos grupos con infección grave. Conclusiones: La infección por SARS-CoV-2 es de evolución más grave en los pacientes con ECV.

Analysis of cardiovascular disease factors on SARS-CoV-2 infection severity

Background:At present, COVID-19 is a global pandemic and is seriously harmful to humans. In this retrospective study, the aim was to investigate the interaction between CVD and COVID-19.Methods:A total of 180 patients diagnosed with COVID-19 in Yichang Central People's Hospital from 29 January to 17 March 2020 were initially included. The medical history, clinical manifestations at the time of admission, laboratory test results, hospitalization time and complications were recorded. According to the medical history, the patients were assigned to the nonsevere group with non-CVD (n=90), the nonsevere group with CVD (n=22), the severe group with non-CVD (n=40) and the severe group with CVD (n=28).Results:In the severe group, compared with non-CVD patients, CVD patients had a significantly higher incidence of fever (P<0.05). However, compared with the nonsevere group, the severe group had significantly higher proportions of patients with hypertension, type 2 diabetes mellitus, CHD and HF (all P<0.05). Among the patients with nonsevere COVID-19, the WBC count and the levels of IL-6, CRP, D-dimer, NT-proBNP, and FBG were significantly higher and the Hb level was significantly lower in the CVD patients than in the non-CVD patients (all P<0.05). However, among the patients with severe COVID-19, only the level of NT-proBNP was significantly higher in CVD patients than in non-CVD patients (P<0.05). In addition, the WBC count and the levels of IL-6, CRP, D-dimer, CKMB, ALT, AST, SCR, NT-proBNP, and FBG were significantly higher and the Hb level was significantly lower in the severe group than in the nonsevere group (all P<0.05). (AU)

Antecedentes:La infección por SARS-CoV-2 está provocando graves consecuencias en la humanidad. El objetivo de este estudio retrospectivo fue investigar el impacto de las enfermedades cardiovasculares (ECV) en la gravedad de dicha infección.Métodos:Entre el 29 de enero y el 17 de marzo de 2020, se diagnosticaron 180 pacientes con neumonía por SARS-CoV-2 en el Hospital Popular Central de Yichang. Se registraron los antecedentes, manifestaciones clínicas, resultados de laboratorio, tiempo de hospitalización y complicaciones. Los pacientes se dividieron en cuatro grupos: 1) infección no grave sin ECV (n=90), 2) infección no grave con ECV (n=22), 3) infección grave sin ECV (n=40) y 4) infección grave con ECV (n=28).Resultados:La prevalencia de fiebre en los pacientes con ECV fue significativamente mayor que en aquellos sin ECV (P<0,05). Sin embargo, en comparación con los pacientes no graves, la proporción de pacientes con hipertensión, diabetes mellitus tipo 2, cardiopatía coronaria e insuficiencia cardíaca en los pacientes graves fue significativamente mayor (p<0,05). Los niveles de recuento de leucocitos, IL-6, PCR, dímero D, NT-proBNP y glucemia en ayunas (GA) en pacientes con ECV fueron significativamente mayores que en los de pacientes sin ECV, aunque los niveles de Hb fueron significativamente menores que los de los pacientes sin ECV (p<0,05). Sin embargo, los valores de NT-proBNP en pacientes con ECV fueron significativamente mayores que en los pacientes sin ECV (P<0,05). (AU)

The critical role and molecular mechanisms of ferroptosis in antioxidant systems: a narrative review.

Background and Objective: Ferroptosis is a recently discovered form of cell death which differs from other forms of cell death in terms of morphology, biochemistry, and regulatory mechanisms. Ferroptosis is regulated by a complex system and the precise molecular mechanisms are still being elucidated. Over the past few years, extensive research has revealed that the essence of ferroptosis is iron-dependent accumulation of lipid hydroperoxides induced by oxidative stress, and the System Xc-glutathione (GSH)-glutathione peroxidase 4 (GPX4) pathway is the main ferroptosis prevention system. Meanwhile, other antioxidant systems have also been implicated in regulating ferroptosis, including the transsulfuration pathway, mevalonate pathway, ferroptosis inhibitory protein 1 (FSP1)-Coenzyme Q10 (CoQ10) pathway, dihydroorotate dehydrogenase (DHODH)-dihydroubiquione (CoQH2) pathway, and GTP cyclohydrolase-1 (GCH1)-tetrahydrobiopterin (BH4) pathway. This article reviews the molecular mechanisms of ferroptosis and its critical role in antioxidant systems, aiming to reveal that antioxidation is an important method of inhibiting ferroptosis and to provide a new direction for the treatment of ferroptosis-related diseases. Methods: We searched all original papers and reviews about the molecular mechanisms of ferroptosis in antioxidant systems using PubMed to November 2021. The search terms used included: 'ferroptosis', 'ferroptosis inducers', 'ferroptosis inhibitors', 'ferroptosis and GSH', 'ferroptosis and GPX4', 'ferroptosis and System Xc-', 'SLC7A11', 'P53', 'NRF2 and ferroptosis', 'iron metabolism', 'lipid peroxidation', 'antioxidant systems', 'transsulfuration pathway', 'mevalonate pathway', 'FSP1-CoQ10', 'DHODH-CoQH2', and 'GCH1-BH4'. Key Content and Findings: We first introduced the origin of ferroptosis and its common inhibitors and inducers. Next, we discussed the molecular mechanisms of ferroptosis and its role in antioxidant systems in existing studies. Finally, we briefly summarized the relationship between ferroptosis and diseases. It reveals that antioxidation is an important method of inhibiting ferroptosis. Conclusions: This review discusses the recent rapid progress in the understanding of the molecular mechanisms of ferroptosis and its role in several antioxidant systems.

Permanent His-bundle pacing in the right atrium in a patient with a Mobitz II atrioventricular block: a case presentation.

BACKGROUND: This case report presents a patient diagnosed with sick sinus syndrome who was successfully treated with permanent His-bundle pacing (PHBP). CASE PRESENTATION: A 36-year-old man was transferred to our hospital due to recurrent syncope. He was diagnosed with sick sinus syndrome based on the 24-h Holter and a history of syncope. He was admitted to hospital and successfully treated with PHBP. The postoperative examination showed that the pacing rhythm, pacemaker pacing and perception function were normal. He was discharged without any complications after a successful pacemaker implantation. CONCLUSIONS: We described a case in which PHBP may become an optimal approach to the management of patients with sick sinus syndrome. Right ventricular pacing has been attempted with inconsistent efficacy outcomes. HBP provides a promising alternative pacing option that might provide symptom resolution to patients with sick sinus syndrome.

Analysis of cardiovascular disease factors on SARS-CoV-2 infection severity.

BACKGROUND: At present, COVID-19 is a global pandemic and is seriously harmful to humans. In this retrospective study, the aim was to investigate the interaction between CVD and COVID-19. METHODS: A total of 180 patients diagnosed with COVID-19 in Yichang Central People's Hospital from 29 January to 17 March 2020 were initially included. The medical history, clinical manifestations at the time of admission, laboratory test results, hospitalization time and complications were recorded. According to the medical history, the patients were assigned to the nonsevere group with non-CVD (n=90), the nonsevere group with CVD (n=22), the severe group with non-CVD (n=40) and the severe group with CVD (n=28). RESULTS: In the severe group, compared with non-CVD patients, CVD patients had a significantly higher incidence of fever (P<0.05). However, compared with the nonsevere group, the severe group had significantly higher proportions of patients with hypertension, type 2 diabetes mellitus, CHD and HF (all P<0.05). Among the patients with nonsevere COVID-19, the WBC count and the levels of IL-6, CRP, D-dimer, NT-proBNP, and FBG were significantly higher and the Hb level was significantly lower in the CVD patients than in the non-CVD patients (all P<0.05). However, among the patients with severe COVID-19, only the level of NT-proBNP was significantly higher in CVD patients than in non-CVD patients (P<0.05). In addition, the WBC count and the levels of IL-6, CRP, D-dimer, CKMB, ALT, AST, SCR, NT-proBNP, and FBG were significantly higher and the Hb level was significantly lower in the severe group than in the nonsevere group (all P<0.05). However, among the patients with severe COVID-19, the incidences of acute myocardial injury, acute kidney injury, arrhythmia, and sudden death were significantly higher in the CVD group than in the non-CVD group (all P<0.05). The same results were found in the comparison of the nonsevere group with the severe group. Among the patients with nonsevere COVID-19, those without CVD had a mean hospitalization duration of 25.25 (SD 7.61) days, while those with CVD had a mean hospitalization duration of 28.77 (SD 6.11) days; the difference was significant (P<0.05). The same results were found in the comparison of the severe group. CONCLUSIONS: CVD affects the severity of COVID-19. COVID-19 also increases the risk of severe CVD.

Cellular FADD-like IL-1ß-converting enzyme-inhibitory protein attenuates myocardial ischemia/reperfusion injury via suppressing apoptosis and autophagy simultaneously.

BACKGROUND AND AIMS: Myocardial ischemia/reperfusion injury (MI/RI) is a result of coronary revascularization, and often increases cell apoptosis and autophagy. Downregulated cellular FADD-like-IL-1ß-converting enzyme-inhibitory protein (cFLIP) was associated with development of several myocardial diseases, whether overexpression of cFLIP can attenuate MI/RI remains unclear. This study aimed to determine the effects of cFLIP on apoptosis and autophagy in MI/RI. METHODS AND RESULTS: Ischemia/reperfusion (I/R) rat model and hypoxia/reoxygenation (H/R) cardiomyocytes model were established. Both I/R injury and H/R injury down-regulated expression of two cFLIP isoforms (cFLIPL and cFLIPS), and instigated apoptosis and autophagy simultaneously. Overexpression of cFLIPL and/or cFLIPS led to a significant increase in cardiomyocytes viability in vitro, and also reduced the myocardial infarct volume in vivo, these changes were associated with suppressed apoptosis and autophagy. Mechanistically, overexpression of cFLIP significantly downregulated pro-apoptotic molecules (Caspase-3, -8, -9), and pro-autophagic molecules (Beclin-1 and LC3-II). Moreover, cFLIP significantly suppressed activity of NF-κB pathway to upregulate the expression of Bcl-2, which is the molecular of interplay of apoptosis and autophagy. CONCLUSION: Overexpression of cFLIP significantly attenuated MI/RI both in vivo and vitro via suppression of apoptosis and lethal autophagy. cFLIP can suppress activity of NF-κB pathway, and further upregulated expression of Bcl-2.

Perforation of the atrial wall and aortic sinus after closure of an atrial septal defect with an Atriasept occluder: a case report.

BACKGROUND: While the perforation of the atrial wall and aortic sinus after closure of an atrial septal defect (ASD) is rare, it's life-threatening, with rapid progress and high mortality. To the best of our knowledge, 21 similar cases have been reported since 1976. CASE PRESENTATION: We report a 16-year-old male whose atrial septal defect (ASD) was closed using a 12-mm Amplatzer septal occluder (ASO). Atrial wall and aortic sinus perforation occurred 3 months after transcatheter closure, and the patient was discharged after emergency operation. He was discharged on the 12th postoperative day in good overall condition. CONCLUSIONS: With this case report, we want to illustrate that although percutaneous closure of ASD is regarded as a routine procedure, we should not forget the potentially lethal complications, especially cardiac erosion. Therefore, we should carefully evaluate the risk of erosion before surgery, and careful lifelong follow-up is needed.

Efficacy and safety of genotype-guided antiplatelet therapy versus standard treatment in 4,604 patients with CAD after PCI: a meta-analysis of randomized controlled trials.

Objective: To compare the efficacy and safety of genotype-guided antiplatelet strategy and standard treatment in patient with coronary artery disease (CAD) after percutaneous coronary intervention (PCI). Methods: Relevant studies published in Medline, Embase, CoChrane Library were searched for randomized controlled trials (RCTs) until August 2020. Studies were screened by selection criteria, quality assessed using the Cochrane Collaboration's tool. Data were extracted from the included studies and statistically analyzed by RevMan 5.3 software. Results: Four RCTs involving 4,604 patients were included in this meta-analysis. Compared with the standard treatment group, the pooled results showed that genotype-guided group associated with lower risk of major adverse cardiovascular events (MACE, OR=0.52, 95%CI:0.35-0.78, P =0.001), any bleeding (OR=0.77, 95%CI: 0.62-0.95, P =0.02) and myocardial infarction (MI, OR=0.48, 95%CI:0.33-0.68, P <0.0001). There was no significant difference in death of any cause (OR=0.53, 95%CI: 0.18-1.54, P =0.25), cardiovascular death (OR=0.74, 95%CI:0.48-1.14, P =0.17), target vessel revascularization (OR=0.66, 95%CI:0.39-1.12, P =0.12) and major bleeding events (OR=0.86, 95%CI: 0.58-1.28, P =0.47). Conclusion: Genotype guided antiplatelet therapy could reduce the risk of MACE, MI and any bleeding events in patients with CAD undergone PCI, compared with standard treatment. Therefore, the findings support that implementation of genotype testing to tailor antiplatelet therapy after PCI.

Duration of dual antiplatelet therapy after percutaneous coronary intervention with implantation of second-generation drug-eluting stent: A meta-analysis of randomized controlled trials.

Objective: The optimal duration of dual antiplatelet therapy (DAPT) in patients after PCI with implantation of a drugeluting stent is still controversial. We conducted a meta-analysis to compare the efficacy and safety of short term DAPT (≤ 3 months) followed by P2Y12 inhibitor monotherapy and standard DAPT (12 months) after PCI. Method: Relevant studies published in Medline, Embase, CoChrane Library were searched for randomized controlled trials (RCTs) until November 2019. Studies were screened by selection criteria then quality assessed through the Cochrane Collaboration's tool. Data were extracted from the included studies and statistically analyzed by RevMan 5.3 software. Results: Five RCTs (n=18,357) were included. Compared with standard DAPT, the short term DAPT was associated with a significant decrease in the major bleeding [odds ratio (OR)=0.43, 95% Confidence Interval (CI):0.32-0.58, P <0.00001] and any bleeding [OR=0.56, 95%CI:0.47-0.66, P<0.00001]. There were no significant differences in all-cause death [OR=0.91, 95%CI:0.71-1.16, P =0.45], major adverse cardiac and cerebrovascular event [OR=1.01, 95%CI:0.87-1.17, P =0.91] and stent thrombosis [OR=0.97, 95%CI:0.61-1.54, P =0.91] between with the short term DAPT group and the standard DAPT group. Conclusions: Short term DAPT followed by P2Y12 monotherapy could reduce the risk of bleeding without increasing the incidence of ischemic events after PCI with implantation of second-generation DES compared with standard DAPT. Therefore, short term DAPT may be a promising strategy to balance ischemic events and bleeding complications in patients after PCI.

UCP2 protect the heart from myocardial ischemia/reperfusion injury via induction of mitochondrial autophagy.

Uncoupling protein 2 (UCP2), located in the mitochondrial inner membrane, is a predominant isoform of UCP that expressed in the heart and other tissues of human and rodent tissues. Nevertheless, its functional role during myocardial ischemia/reperfusion (I/R) is not entirely understood. Ischemic preconditioning (IPC) remarkably improved postischemic functional recovery followed by reduced lactate dehydrogenase (LDH) release with simultaneous upregulation of UCP2 in perfused myocardium. We then investigated the role of UCP2 in IPC-afforded cardioprotective effects on myocardial I/R injury with adenovirus-mediated in vivo UCP2 overexpression (AdUCP2) and knockdown (AdshUCP2). IPC-induced protective effects were mimicked by UCP2 overexpression, while which were abolished with silencing UCP2. Mechanistically, UCP2 overexpression significantly reinforced I/R-induced mitochondrial autophagy (mitophagy), as measured by biochemical hallmarks of mitochondrial autophagy. Moreover, primary cardiomyocytes infected with AdUCP2 increased simulated ischemia/reperfusion (sI/R)-induced mitophagy and therefore reversed impaired mitochondrial function. Finally, suppression of mitophagy with mdivi-1 in cultured cardiomyocytes abolished UCP2-afforded protective effect on sI/R-induced mitochondrial dysfunction and cell death. Our data identify a critical role for UCP2 against myocardial I/R injury through preventing the mitochondrial dysfunction through reinforcing mitophagy. Our findings reveal novel mechanisms of UCP2 in the cardioprotective effects during myocardial I/R.

Abnormal circadian rhythms are associated with plaque instability in acute coronary syndrome patients.

AIM: Acute coronary syndrome (ACS), a leading cause of morbidity and mortality worldwide, is among the most serious cardiovascular diseases. Circadian rhythms are present in almost all organisms. In clinical practice, we have found that ACS is closely related to these circadian rhythms. However, the relationship between circadian rhythms and plaque instability in ACS patients is incompletely understood. The aim of this study is to provide new insights into the relationship between circadian rhythms and plaque instability in ACS patients. METHODS: We enrolled patients with ACS and individuals with normal coronary artery function in this study. The Athens Insomnia Scale (AIS), Pittsburgh Sleep Quality Index (PSQI), International Physical Activity Questionnaire (IPAQ) and Healthy Diet Score (HDS) were used to evaluate circadian rhythms. Furthermore, quantitative real-time polymerase chain reaction (qRT-PCR) was used to assess the mRNA expression levels of muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1), circadian locomotor output cycles kaput (Clock), Cryptochrome1 (Cry1), Period2 (Per2), nuclear receptor subfamily 1, group D, member 1 (Rev-erbα), and matrix metalloproteinases MMP2 and MMP9. RESULTS: AIS scores and PSQI scores were significantly higher in patients with ST segment elevation myocardial infarction (STEMI), non-ST segment elevation myocardial infarction (NSTEMI), and unstable angina pectoris (UA) than in the normal controls (NCs) (P < 0.05). The IPAQ scores of the NCs and patients with UA were significantly higher than in patients with STEMI and NSTEMI (P < 0.05). Notably higher HDS scores were recorded for the NCs compared to those of patients with UA, NSTEMI, and STEMI (P < 0.05). Consistent with these findings, compared with the NCs, the lowest levels of Bmal1, Clock, Cry1, Per2 and Rev-erbα mRNAs were detected in patients with STEMI, followed by patients with NSTEMI and then patients with UA (P < 0.05). Furthermore, the levels of MMP2 and MMP9 mRNA were significantly higher in the patients with STEMI, NSTEMI, and UA than those in the NCs (P < 0.05). In addition, we found that the levels of MMP mRNA negatively correlated with the levels of clock genes mRNAs (P < 0.05, respectively). CONCLUSIONS: Based on our data, the circadian rhythms and clock genes are correlatively with the occurrence of ACS, and the expression levels of clock genes are negatively correlated with plaque stability in ACS patients.

The Effects of High Mobility Group Box-1 Protein on Peripheral Treg/Th17 Balance in Patients with Atherosclerosis.

BACKGROUND: Atherosclerosis (AS) is defined as chronic inflammation of the vessel wall. The major objective of the this study was to explore the mechanism of Treg/Th17 imbalance and the role of high mobility group box-1 protein (HMGB1) on the balance in AS. METHODS: We detected the apoptotic ratios of Treg and Th17 cells in peripheral blood mononuclear cells (PBMCs) from subjects with AS and normal coronary arteries (NCA) by flow cytometry. The effects of recombinant HMGB1 (rHMGB1) on the proportion, apoptosis and differentiation of Treg and Th17 cells were analyzed using flow cytometry, qRT-PCR and ELISA. RESULTS: The frequencies of apoptotic Treg cells in the PBMCs from the subjects with AS were significantly higher than in those with NCA (p < 0.01). Stimulation of rHMGB1 obviously increased the level of Th17 cells and acid- related orphan receptor C (RORC) mRNA, and markedly decreased Treg cell frequency and the mRNA expression of factor forkhead family protein 3 (Foxp3) in the PBMCs. rHMGB1 played an obvious role in elevating Treg cell apoptosis ratio (p < 0.01). rHMGB1 treatment significantly decreased Treg cell ratio and IL-10 level, and increased Th17 cell ratio and IL-17A level induced from naïve CD4+ T cells. CONCLUSIONS: HMGB1 may modulate Treg/Th17 balance in patients with AS through inducing Treg cell apoptosis and promoting cell differentiation of Th17.

Down-Regulation of miR-327 Alleviates Ischemia/Reperfusion-Induced Myocardial Damage by Targeting RP105.

BACKGROUND/AIMS: Micro RNAs (miRNAs) play a very important role in myocardial ischemia/ reperfusion injury (MIRI), including in inflammation, apoptosis, and angiogenesis. Previous studies have demonstrated up-regulation of miR-327 in renal ischemia/reperfusion injury and MIRI. Via TargetScan, we found RP105 is a possible target gene of miR-327; our previous studies have also confirmed that RP105 acted as a cardioprotective protein in MIRI by reducing inflammation. However, the regulatory effect of miR-327 on RP105 has not previously been proposed. In our study, we aimed to identify the regulatory effect of miR-327 on RP105 protein in MIRI rats. METHODS: Sixty male Sprague-Dawley rats were randomly divided into five groups, which were pre-treated with saline (sham and ischemia/reperfusion group), adenovirus-expressing miR-327-RNAi (Ad-miR-327-i group), control (Ad-NC group), or pri-miR-327 (Ad-miR-327 group) treatments. Three days later, the rat MIRI model was established by ischemia for 30 min, followed by reperfusion for 3 h. Myocardium and plasma were harvested and assessed. RESULTS: miR-327 was increased by nearly 3-fold both in myocardium and plasma, which down-regulated RP105 in a 3'-untranslated region-dependent manner, and down-regulation of miR-327 via adenovirus transfection indirectly suppressed the TLR4/ TLR2-MyD88-NF-κB signaling axis activation via up-regulation of RP105, which subsequently resulted in reduced myocardial infarct size, attenuated cardiomyocyte destruction, and alleviated inflammation. In contrast, up-regulation of miR-327 induced the opposite effect. CONCLUSION: Down-regulation of miR-327 exerts a cardioprotective effect against MIRI by reducing inflammation, which may constitute a promising molecular therapeutic target for treating MIRI.

Glycyrrhizin, a High-Mobility Group Box 1 Inhibitor, Improves Lipid Metabolism and Suppresses Vascular Inflammation in Apolipoprotein E Knockout Mice.

BACKGROUND: High-mobility group box protein 1 (HMGB1) is known to have proinflammatory properties; however, the mechanisms by which HMGB1 influences immune responses during atherosclerosis (AS) development are not well understood. Thus, this study investigated the relationship between HMGB1 and vascular inflammation in Apoe-/- mice and whether glycyrrhizin (GLY), a small inhibitor of HMGB1, could have atheroprotective effects in AS. METHODS: Apoe-/- mice on a high-fat diet were treated with GLY (50 mg/kg) or vehicle by gavage once daily for 12 weeks, respectively. RESULTS: The GLY group exhibited significantly decreased serum lipid levels, atherosclerotic plaque deposition, and serum HMGB1 levels, as well as an increased Treg/Th17 ratio. The GLY group displayed increased interleukin-10 (IL-10) and IL-2 expression and decreased IL-17A and IL-6 expression. Furthermore, the GA treatment significantly reduced STAT3 phosphorylation in Th17 cells and increased STAT5 phosphorylation in Treg cells. CONCLUSIONS: Our findings indicate that the attenuation of atherosclerotic lesions in Apoe-/- mice by GLY might be associated with the amelioration of lipid metabolism abnormalities, inhibition of HMGB1 expression, and alterations in the Treg/Th17 ratio.

RNAi-Mediated Down-Regulation of CD47 Protects against Ischemia/Reperfusion-Induced Myocardial Damage via Activation of eNOS in a Rat Model.

BACKGROUND/AIMS: Oxidative stress is strongly implicated in the pathogenesis of myocardial damage caused by ischemia reperfusion (I/R). Previous studies have confirmed that cardiac CD47 drives left ventricular heart failure. However, the role for CD47 in myocardial I/R injury (MIRI) has not previously been proposed. This study was designed to investigate whether down-regulation of CD47 using RNA interference (RNAi) technology can relieve inhibition of nitric oxide signaling and attenuate myocardial damage in a rat model of I/R. METHODS: Male Sprague-Dawley rats (n = 40) were randomly allocated to four groups and pre-treated either with saline (Sham and I/R groups), or adenovirus expressing either control (Ad-EGFP-N) or CD47-targeting (Ad-EGFP-CD47) RNAi. After four days, the rat MIRI model was established by occluding the left anterior descending coronary artery for 30 min, followed by reperfusion for 3 h. Heart tissue was harvested and assessed by immunohistochemistry, western blot, and quantitative RT-PCR. Outcome measures included infarct size, myocardial enzyme (creatine kinase, creatine kinase-MB, and lactate dehydrogenase) levels in serum, markers of oxidative stress, and morphological changes to the myocardium. RESULTS: Delivery of Ad-EGFP-CD47 RNAi into the myocardium remarkably decreased CD47 expression levels. Down-regulation of CD47 was significantly associated with reduced infarct size and serum levels of myocardial enzymes, increased activity of endothelial nitric oxide synthase, increased levels of nitric oxide, and decreased levels of oxidative stress. CONCLUSION: These data indicate that down-regulation of CD47 exerts a protective effect against MIRI, which may be attributable to attenuation of oxidative stress via activation of the eNOS/NO signaling pathway.

Radioprotective 105 kDa protein attenuates ischemia/reperfusion-induced myocardial apoptosis and autophagy by inhibiting the activation of the TLR4/NF-κB signaling pathway in rats.

Toll-like receptor 4 (TLR4) serves as an important inducer of apoptotic and autophagic responses in myocardial ischemia/reperfusion (I/R) injury (MIRI). Radioprotective 105 kDa protein (RP105) is a specific inhibitor of TLR4. However, the molecular mechanisms by which RP105 represses myocardial apoptosis and autophagy through TLR4­mediated signaling during I/R have not yet been fully elucidated. Therefore, in the present study, we aimed to examine whether adenovirus-mediated RP105 overexpression repressed myocardial apoptosis and autophagy by inhibiting the TLR4-driven mechanism in MIRI. Three days after the injection of virus or saline into the myocardium, Sprague-Dawley (SD) rats were subjected to 30 min of left anterior descending coronary artery occlusion and 6 h of reperfusion. Myocardial specimens were prepared for analysis. We performed immunohistochemichal and histopathological analysis, the measurement of cardiac biomarkers, TUNEL assay , RT-qPCR and western blot analysis. The results indicated that the overexpression of RP105 contributed to an amelioration of myocardial histological damage, decreased leakage of creatine kinase (CK) and lactate dehydrogenase (LDH), as well as a reduction in the number of TUNEL-positive cardiomyocytes. The levels of positively associated modulators of apoptosis and autophagy were also significantly downregulated by RP105, whereas Bcl-2, which plays an opposite role in inducing apoptosis and autophagy, was inversely upregulated. Furthermore, the overexpression of RP105 led to the repression of TLR4 activity and the phosphorylation of NF-κB/p65, as well as the reduced production of the cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α). Taken together, these data suggest that RP105 protects the myocardium against apoptosis and autophagy, and plays a cardioprotective role during I/R injury. This is most likely due to the inactivation of TLR4/NF-κB signaling pathway. Thus, RP105 may represent an innovative therapeutic target for attenuating MIRI.