Prediction of the left ventricular mass index in hypertensive patients using the product of red cell distribution width and mean corpuscular volume.

The product of red cell distribution width (RDW) and mean corpuscular volume (MCV) has been identified as an indicator of target organ damage in cases of hypertension. However, the role of the RDW-MCV product in assessing carotid alteration, renal damage, and left ventricular hypertrophy in patients with hypertension has not been elucidated. In this cross-sectional study, a total of 1115 participants with hypertension were included. The RDW and MCV at admission were measured using an automated hematology analyzer. Organ damage was determined by the left ventricular mass index (LVMI), carotid intima-media thickness, and estimated glomerular filtration rate. The prevalence rates of carotid alteration and left ventricular hypertrophy were 57.0% and 18.0%, respectively. A higher RDW-MCV product and RDW were observed in hypertensive patients who developed carotid alteration. After adjusting for potential confounding factors, the correlations of the RDW-MCV product (P = .285) and RDW (P = .346) with carotid alteration were not significant. Moreover, the analysis of variance showed no significant correlation between RDW and LVMI (P = .186). However, the RDW-MCV product was higher in individuals with a high LVMI compared to those with a normal LVMI. Multivariable linear regression analysis revealed that the RDW-MCV product was independently associated with the LVMI (ß = 2.519, 95% CI: 0.921-4.116; P = .002), but not the estimated glomerular filtration rate (ß = -0.260, 95% CI: -2.031-1.511; P = .773). An elevated RDW-MCV product may be a predictor for left ventricular hypertrophy in patients with hypertension.

Sirtuin 2 Exerts Regulatory Functions on Radiation-Induced Myocardial Fibrosis in Mice by Mediating H3K27 Acetylation of Galectin-3 Promoter.

Background: Sirtuin 2 (SIRT2) and galectin-3 have been shown to protect the heart against fibrosis. However, their impacts on radiation-induced myocardial fibrosis (RIMF) remain to be elucidated. To deepen this understanding, the current study sought to explore the effects of SIRT2 and galectin-3 on RIMF and the underlying mechanisms. Methods: Galectin-3 knockout mice were obtained, and a radiation-induced heart damage (RIHD) mouse model was induced by local radiation exposure to the heart. Lentivirus transfection was then performed, and heart function, fibrosis of heart tissues, and levels of SIRT2, galectin-3, and fibrosis-related markers collagen type-I/-III and matrix metalloproteinase (MMP)2/MMP9 were respectively assessed by echocardiography, hematoxylin-eosin and Masson staining, reverse transcription-quantitative polymerase chain reaction, Western blot, and immunofluorescence staining. Additionally, Western blot and chromatin immunoprecipitation were used to test H3K27 acetylation levels and the binding of H3K27ac to galectin-3, respectively. Results: After radiation exposure, heart tissues from the galectin-3 knockout mice had a smaller fibrotic area compared to normal mice, with reduced expression levels of collagen type-I/-III and MMP2/MMP9. SIRT2 was down-regulated and galectin-3 was up-regulated after RIHD treatment. The histone deacetylase inhibitor sirtinol promoted galectin-3 expression and H3K27 acetylation in a time-dependent manner, and increased H3K27ac enrichment in the galectin-3 promoter. Overexpression of SIRT2 down-regulated H3K27ac, collagen type-I/-III, and MMP2/MMP9 expression levels, and reduced the fibrotic area in mouse heart tissues. However, these effects were reversed by the additional overexpression of galectin-3. Conclusions: SIRT2 facilitates deacetylation of H3K27 to inhibit galectin-3 transcription, thus ameliorating RIMF in mice.

Safety and efficacy of the DragonFly system for transcatheter valve repair of degenerative mitral regurgitation: one-year results of the DRAGONFLY-DMR trial.

BACKGROUND: Severe degenerative mitral regurgitation (DMR) can cause a poor prognosis if left untreated. For patients considered at prohibitive surgical risk, transcatheter edge-to-edge repair (TEER) has become an accepted alternative therapy. The DragonFly transcatheter valve repair system is an innovative evolution of the mitral TEER device family to treat DMR. AIMS: Herein we report on the DRAGONFLY-DMR trial (ClinicalTrials.gov: NCT04734756), which was a prospective, single-arm, multicentre study on the safety and effectiveness of the DragonFly system. METHODS: A total of 120 eligible patients with prohibitive surgical risk and DMR ≥3+ were screened by a central eligibility committee for enrolment. The study utilised an independent echocardiography core laboratory and clinical event committee. The primary endpoint was the clinical success rate, which measured freedom from all-cause mortality, mitral valve reintervention, and mitral regurgitation (MR) >2+ at 1-year follow-up. RESULTS: At 1 year, the trial successfully achieved its prespecified primary efficacy endpoint, with a clinical success rate of 87.5% (95% confidence interval: 80.1-92.3%). The rates of major adverse events, all-cause mortality, mitral valve reintervention, and heart failure hospitalisation were 9.0%, 5.0%, 0.8%, and 3.4%, respectively. MR ≤2+ was 90.4% at 1 month and 92.0% at 1 year. Over time, left ventricular reverse remodelling was observed (p<0.05), along with significant improvements in the patients' functional and quality-of-life outcomes, shown by an increase in the New York Heart Association Class I/II from 32.4% at baseline to 93.6% at 12 months (p<0.001) and increased Kansas City Cardiomyopathy Questionnaire (KCCQ) score of 31.1±18.2 from baseline to 12 months (p<0.001). CONCLUSIONS: The DRAGONFLY-DMR trial contributes to increasing evidence supporting the safety and efficacy of TEER therapy, specifically the DragonFly system, for treating patients with chronic symptomatic DMR 3+ to 4+ at prohibitive surgical risk.

The active pulling technique to solve microcatheter-uncrossable lesions in retrograde chronic total occlusion percutaneous coronary intervention.

BACKGROUND: It is not uncommon to encounter retrograde microcatheter-uncrossable lesions in retro-recanalization of Chronic Total Occlusion (CTO) cases, existing solutions were time-consuming or complicated to operate. Therefore, the present study aimed to propose and evaluate the feasibility, safety of a novel technique termed Active Pulling retrograde microcatheter crossing Technique (APT) during retrograde CTO percutaneous coronary intervention (PCI). METHODS: We retrospectively collected retrograde CTO-PCI cases from February 2017 to April 2023, only cases with the retrograde wire successfully crossed the CTO lesion were analyzed. The baseline clinical characteristics, angiographic characteristics, procedural details, and in-hospital major adverse cardiac events (MACEs) were compared. RESULTS: A total of 80 CTO cases were divided into the APT group and the non-APT group according to whether the APT was applied in the procedure. The APT group had a higher rate of device success than the non-APT group (100% vs. 85%, P = 0.013), with shorter duration (5.3 ± 3.8 vs. 18.6 ± 5.9 min, P < 0.001) and a smaller number of retrograde microcatheters were used (P < 0.001). In the APT group, the average air kerma radiation exposure was lower (2.7 ± 1.2 vs. 4.3 ± 1.7 Gy, P < 0.001), the fluoroscopy time (69.0 ± 15.0 vs. 88.1 ± 18.9 min, P < 0.001) and the procedure time (116.2 ± 22.2 vs. 131.6 ± 28.7 min, P = 0.009) was shorter than the non-APT group. The technical success rate of both groups reached 100% while the procedure success rate was higher in the APT group than the non-APT group (100% vs. 85%, P = 0.13). CONCLUSIONS: The APT is an easy and safe technique that can greatly improve procedural efficiency without adding other instruments, and allows the retrograde microcatheter to quickly crossing the CTO body after successful retrograde wire externalization.

Potential therapeutic effect of olfactory ensheathing cells in neurological diseases: neurodegenerative diseases and peripheral nerve injuries.

Neurological diseases are destructive, mainly characterized by the failure of endogenous repair, the inability to recover tissue damage, resulting in the increasing loss of cognitive and physical function. Although some clinical drugs can alleviate the progression of these diseases, but they lack therapeutic effect in repairing tissue injury and rebuilding neurological function. More and more studies have shown that cell therapy has made good achievements in the application of nerve injury. Olfactory ensheathing cells (OECs) are a special type of glial cells, which have been proved to play an important role as an alternative therapy for neurological diseases, opening up a new way for the treatment of neurological problems. The functional mechanisms of OECs in the treatment of neurological diseases include neuroprotection, immune regulation, axon regeneration, improvement of nerve injury microenvironment and myelin regeneration, which also include secreted bioactive factors. Therefore, it is of great significance to better understand the mechanism of OECs promoting functional improvement, and to recognize the implementation of these treatments and the effective simulation of nerve injury disorders. In this review, we discuss the function of OECs and their application value in the treatment of neurological diseases, and position OECs as a potential candidate strategy for the treatment of nervous system diseases.

Inclisiran: a new generation of lipid-lowering siRNA therapeutic.

Atherosclerotic heart disease (AHD) is a major cause of morbidity and mortality worldwide. Lowering low-density lipoprotein cholesterol (LDL-C) levels is a key strategy to prevent and treat AHD. Inclisiran is a novel siRNA drug that targets proprotein convertase subtilisin/kexin type 9 (PCSK9) gene expression and reduces LDL-C levels with only two or three injections per year. This review summarizes the mechanism, efficacy, safety, and applications of Inclisiran in various populations and settings, based on recent literature. It also compares Inclisiran with other lipid-lowering drugs, especially other PCSK9 inhibitors. We conclude that Inclisiran is a promising lipid-lowering agent that can provide convenience and effectiveness for patients with high cardiovascular risk. However, some challenges and limitations remain for Inclisiran, such as its long-term safety and efficacy, its cost-effectiveness and accessibility, and its interactions and synergies with other drugs. These issues need further investigation and evaluation in future studies.

Downregulation of MicroRNA-29-3p Following Percutaneous Coronary Intervention: An Implication of YY1/IRAK1 Pathway in the Post-Vascular Injury Inflammation.

This study explored the expression of microRNA (miR)-29b-3p following percutaneous coronary intervention (PCI) and the implication of its downstream Yin Yang 1 (YY1)/interleukin (IL)-1 receptor-associated kinase 1 (IRAK1) pathway in post-vascular injury inflammation. Blood samples were collected for analysis of plasma miR-29b-3p from patients with acute coronary syndrome before surgery, 1 day after PCI, and 30 days after PCI. Lipopolysaccharide (LPS)-treated human coronary artery endothelial cells (HCAECs) were transfected with miR-29b-3p mimic/inhibitor or YY1 shRNA and underwent viability tests. Enzyme-linked immunosorbent assay was performed to detect the levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), IL-1ß, IL-6, and tumor necrosis factor (TNF)-α in serum and cell culture supernatant. Dual-luciferase reporter and RNA/chromatin immunoprecipitation were used to confirm the targeting relationships among miR-29b-3p, YY1, and IRAK1. A rat model of intraluminal injury of the common femoral artery was established to address the role of miR-29b-3p and relevant mechanisms. miR-29b-3p was lowly expressed, and sVCAM-1, IL-1ß, IL-6, and TNF-α were upregulated 1 day after PCI and 24 h after LPS treatment. miR-29b-3p overexpression or YY1 knockdown alleviated LPS-induced inflammatory responses and improved the viability of HCAECs. miR-29b-3p inhibition aggravated LPS-induced inflammatory injury in HCAECs. miR-29b-3p bound to YY1 mRNA and inhibited the expression of YY1 protein. YY1 bound to the IRAK1 promoter and activated the transcription of IRAK1. Upregulation of miR-29b-3p suppressed the inflammatory response after intraluminal injury of the common femoral artery in rats. In conclusion, dysregulation of the YY1/IRAK1 pathway via miR-29b-3p downregulation may be implicated in post-vascular injury inflammation.

Prognostic value of quantitative flow ratio in patients with coronary heart disease after percutaneous coronary intervention therapy: a meta-analysis.

Background: Coronary atherosclerotic heart disease is one of the most serious health and life-threatening diseases. There is no doubt that despite the increasing number of assessment methods used clinically, the prognosis assessment is still not ideal, and newer assessment methods are needed. Objective: To investigate the predictive value of quantitative flow ratio (QFR) for adverse events (vessel-oriented composite endpoint events/target lesion failure) in patients after percutaneous coronary intervention (PCI). Method: Eight studies involving 4,173 patients (5,688 vascular lesions) were included. These are studies on the relationship between QFR values and prognosis of adverse cardiac events after PCI. This meta-analysis was performed after quality assessment and data extraction of clinical trials data that met the inclusion criteria. Result: Each of the eight studies described the cut-off values for the best predictive ability of post-PCI QFR and the hazard ratio (HR) between QFR values and adverse events, respectively. The pooled HR of these studies was 4.72 (95% CI: 3.29-6.75). Concurrently, lower post-PCI QFR values were associated with the occurrence of individual clinical events (cardiac death/myocardial infarction/target vessel revascularization), with relative risk values of 6.51 (95% CI: 4.96-8.53), 4.83 (95% CI: 3.08-7.57), and 4.21 (95% CI: 2.66-6.68), respectively. Conclusion: QFR may have great potential in the assessment of prognosis. It is necessary to measure QFR value after PCI. A lower QFR value after PCI was an important predictor for experiencing adverse events.

RNA methylation reading protein YTHDF2 relieves myocardial ischemia-reperfusion injury by downregulating BNIP3 via m6A modification.

BNIP3 is reported to be involved in hypoxia-induced mitochondrial defect and cell death in cardiomyocytes. However, little is known about the specific function and molecular mechanism of BNIP3-mediated mitophagy in myocardial ischemia-reperfusion injury (MIRI). Herein, this study explored the mechanism regulating BNIP3-modulated mitophagy in MIRI. Rat cardiomyocytes (H9c2 cells) underwent transfection and hypoxia/reoxygenation (H/R) treatment, followed by cell viability and apoptosis detection. Gain-of-function assays were conducted in rats before MIRI modeling, followed by the monitoring of cardiac changes and the evaluation of cardiac function, myocardial infarction area, and apoptosis in myocardial tissues. The levels of creatine kinase MB (CK-MB), cardiac troponin I (cTnI), lactic dehydrogenase (LDH), reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), p62, and LC3 II/LC3 I were tested in rat serum or H9c2 cells. The co-localization of LC3 and TOMM20 was analyzed. The interaction of BNIP3 with YTHDF2 was assessed. H/R treatment decreased cell viability and p62 and SOD levels while elevating cell apoptosis, the levels of CK-MB, cTnI, LDH, MDA, ROS, and LC3 II/LC3 I, the number of autophagosomes, and the co-localization of LC3 and TOMM20 in cardiomyocytes, which were neutralized by downregulating BNIP3 or upregulating YTHDF2. Moreover, upregulation of YTHDF2 repressed myocardial injury and mitophagy in MIRI rats. Mechanistically, YTHDF2 mediated BNIP3 expression by recognizing methylated BNIP3. Upregulation of BNIP3 counteracted the suppressive effect of YTHDF2 overexpression on H/R-induced injury and mitophagy in cardiomyocytes. The RNA methylation reading protein YTHDF2 ameliorated MIRI by downregulating BNIP3 via m6A modification.

Analgesic drug use in patients with STEMI: Current perspectives and challenges.

Therapy for patients with ST-elevation myocardial infarction (STEMI) has been a controversial topic since the introduction of thrombolytic agents in the 1980s. The use of morphine, fentanyl and lidocaine has increased substantially during this period. However, there is still limited evidence on their advantages and limitations. In this review, the clinical application, as well as future considerations of morphine, fentanyl and lidocaine in patients with ST segment elevation myocardial infarction were discussed.

Analysis of risk factors for postoperative acute cerebral infarction in patients with type B aortic dissection.

OBJECTIVE: To study risk factors of postoperative acute cerebral infarction (PACI) in patients with type B aortic dissection (TB-AD). METHODS: The data of 36 patients with TB-AD and PACI undergoing endovascular aortic repair (EVAR) from Mar 2018 and Mar 2021 were collected as the PACI group retrospectively. The data of 114 TB-AD patients without PACI were collected as the control group retrospectively. The medical history, surgery-related indicators, general data, imaging data and laboratory test results (D-dimer (D-D), preoperative serum creatinine and preoperative white blood cell count) were compared. Then, logistic regression was applied to analyze risk factors for PACI in TB-AD patients. RESULTS: The surgery time, blood loss and hospital stay of patients in the PACI group were determined to be obviously higher/longer when comparing to those in the control group. Aortic arch radius of curvature and length of proximal anchoring zone showed no significant difference between the two groups. Pearson correlation analysis indicated that D-D level after surgery was positively related to white blood cell count and serum creatinine level in TB-AD patients. Binary logistic regression analysis showed that operation time, emergency surgery, preoperative D-D and preoperative serum creatinine level were independent risk factors for PACI after EVAR in the patients with TB-AD (P < 0.05). CONCLUSION: There are many independent risk factors for PACI after EVAR in patients with TB-AD, and preoperative D-D level and serum creatinine level should be given attention.

Optimal postoperative surveillance strategies for cancer survivors with gastric neuroendocrine carcinoma based on individual risk: a multicenter real-world cohort study.

BACKGROUND: The best follow-up strategy for cancer survivors after treatment should balance the effectiveness and cost of disease detection while detecting recurrence as early as possible. Due to the low incidence of gastric neuroendocrine carcinoma and mixed adenoneuroendocrine carcinoma [G-(MA)NEC], high-level evidence-based follow-up strategies is limited. Currently, there is a lack of consensus among clinical practice guidelines regarding the appropriate follow-up strategies for patients with resectable G-(MA)NEC. MATERIALS AND METHODS: The study included patients diagnosed with G-(MA)NEC from 21 centers in China. The random forest survival model simulated the monthly probability of recurrence to establish an optimal surveillance schedule maximizing the power of detecting recurrence at each follow-up. The power and cost-effectiveness were compared with the National Comprehensive Cancer Network, European Neuroendocrine Tumor Society, and European Society for Medical Oncology Guidelines. RESULTS: A total of 801 patients with G-(MA)NEC were included. The patients were stratified into four distinct risk groups utilizing the modified TNM staging system. The study cohort comprised 106 (13.2%), 120 (15.0%), 379 (47.3%), and 196 cases (24.5%) for modified groups IIA, IIB, IIIA, and IIIB, respectively. Based on the monthly probability of disease recurrence, the authors established four distinct follow-up strategies for each risk group. The total number of follow-ups 5 years after surgery in the four groups was 12, 12, 13, and 13 times, respectively. The risk-based follow-up strategies demonstrated improved detection efficiency compared to existing clinical guidelines. Further Markov decision-analytic models verified that the risk-based follow-up strategies were better and more cost-effective than the control strategy recommended by the guidelines. CONCLUSIONS: This study developed four different monitoring strategies based on individualized risks for patients with G-(MA)NEC, which may improve the detection power at each visit and were more economical, effective. Even though our results are limited by the biases related to the retrospective study design, we believe that, in the absence of a randomized clinical trial, our findings should be considered when recommending follow-up strategies for G-(MA)NEC.

Thioredoxin Reductase 2 Synergizes with Cytochrome c, Somatic to Alleviate Doxorubicin-Induced Oxidative Stress in Cardiomyocytes and Mouse Myocardium.

Doxorubicin (DOX) may cause multiple side effects, which include cardiotoxicity. Hence, to ascertain the impact of thioredoxin reductase 2 (TXNRD2) and cytochrome c, somatic (CYCS) on DOX-induced oxidative stress (OS) in cardiomyocytes and mouse myocardium, this study was implemented. DOX was utilized to treat cardiomyocytes and mice, and TXNRD2 and CYCS expression in cell supernatant and mouse myocardial tissues was detected. TXNRD2 and/or CYCS were overexpressed in DOX-induced cardiomyocytes and mice. In cardiomyocytes, cell viability and the levels of reactive oxygen species (ROS), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), and glutathione (GSH) were measured. In mice, pathologic changes of the heart, ejection fraction (EF), fractional shortening (FS), and heart weight (HW) /tibial length (TL) ratio, and the contents of lactic dehydrogenase (LDH), creatine kinase-MB (CK-MB), and cardiac troponin I (cTnI) were analyzed. To assess the binding between TXNRD2 and CYCS, coimmunoprecipitation and glutathione S-transferase pull-down assays were performed. TXNRD2 and CYCS were downregulated in DOX-treated cardiomyocytes and mice. Mechanistically, TXNRD2 interacted with CYCS. Overexpression of TXNRD2 or CYCS augmented viability and SOD, CAT, and GSH levels but reduced ROS and MDA contents in DOX-induced cardiomyocytes, which was further facilitated by simultaneous overexpression of TXNRD2 or CYCS. Moreover, TXNRD2 or CYCS upregulation improved the pathologic changes in myocardial tissues, along with increases in EF, FS, and HW/TL ratio of the heart and SOD, CAT, and GSH levels and decreases in LDH, CK-MB, cTnI, ROS, and MDA levels. TXNRD2 coordinated with CYCS to alleviate DOX-induced OS in cardiomyocytes and mouse myocardium.

Protein PDK4 Interacts with HMGCS2 to Facilitate High Glucoseinduced Myocardial Injuries.

OBJECTIVES: As a distinct type of cardiomyopathy, diabetic cardiomyopathy (DCM) is featured as diastolic or systolic cardiac dysfunction in diabetic patients. In order to broaden the understanding of molecular mechanisms in DCM, we intended to explore the mechanism of the interaction between PDK4 protein and Hmgcs2 in high glucose (HG)-induced myocardial damage. METHODS: PDK4 and Hmgcs2 expression in the myocardium of diabetes mellitus (DM) model rats and HG-incubated cardiomyocyte line H9C2 was analyzed by western blot analysis. Echocardiography and TUNEL assay were utilized for respective assessment of cardiac structure and function and cardiomyocyte apoptosis in DM rats after silencing PDK4 or/and Hmgcs2. In vitro, the impact of PDK4 and Hmgcs2 on HG-induced cardiomyocyte injuries was identified with cell counting kit-8 and flow cytometry assays, along with detection of LDH release, caspase-3/7 activities, and reactive oxygen species (ROS) and malondialdehyde (MDA) levels. Moreover, a coimmunoprecipitation assay was utilized to test the interaction between PDK4 and Hmgcs2. RESULTS: Both PDK4 and Hmgcs2 were highly expressed in the myocardial tissues of DM rats. Mechanistically, PDK4 interacted with Hmgcs2 to upregulate Hmgcs2 expression in HG-induced H9C2 cells. Silencing PDK4 improved cardiac function and reduced cardiomyocyte apoptosis in DM rats. In HG-induced H9C2 cells, PDK4 or Hmgcs2 silencing enhanced cell viability and reduced LDH release, caspase-3/7 activities, cell apoptosis, and ROS and MDA levels, and these trends were further promoted by the simultaneous silencing of PDK4 and Hmgcs2. CONCLUSION: In summary, the silencing of PDK4 and Hmgcs2 alleviated HG-induced myocardial injuries through their interaction.

MiR-30a-5p Promotes Vein Graft Restenosis by Inhibiting Cell Autophagy through Targeting ATG5.

OBJECTIVE: The aim of the study was to investigate the role of miR-30a-5p in restenosis of rats following vein grafting and the underlying mechanism. METHODS: Vein graft rat models were established and perfused with miR-30a-5p antagomir and si-ATG5 to probe the regulation of miR-30a-5p/ATG5 on intimal hyperplasia. Human saphenous vein smooth muscle cells (HSVSMCs) were obtained from the great saphenous veins of patients undergoing coronary artery bypass grafting and subjected to assays for autophagy, proliferation, and migration after gain and loss of function of miR-30a-5p and/or ATG5. The binding of miR-30a-5p and ATG5 was confirmed by RIP and dual-luciferase reporter assays. RESULTS: MiR-30a-5p expression gradually increased, ATG5 expression gradually decreased, and the intima was increasingly thickened during restenosis of grafted veins. Knockdown of miR-30a-5p in rats repressed the restenosis of vein grafts, while a deficiency of ATG5 reversed the effect of miR-30a-5p inhibition. Upregulation of miR-30a-5p enhanced the proliferation and migration of HSVSMCs and inhibited the autophagy, while downregulation of miR-30a-5p or overexpression of ATG5 showed opposite effects. ATG5 is a target gene of miR-30a-5p. CONCLUSION: MiR-30a-5p exacerbates vein graft restenosis by repressing ATG5 expression and inhibiting autophagy.

The potential function of SP1 and CPPED1 in restenosis after percutaneous coronary intervention.

OBJECTIVES: Impacts of molecular pathways have been discussed recently on restenosis after percutaneous coronary intervention (PCI). Hence, this study aimed to explore the impact of calcineurin-like phosphoesterase domain containing 1 (CPPED1) and specificity protein 1 (SP1) on restenosis after PCI. METHODS: A carotid balloon injury rat model was established, followed by western blot analysis of SP1 and CPPED1 expression in carotid artery (CA) tissues. After SP1 and CPPED1 were overexpressed, the neointimal hyperplasia and luminal stenosis were assessed. In addition, EPC underwent hypoxia/reoxygenation (H/R) treatment to construct an endothelial injury cell model. Then, cell proliferation, apoptosis, intracellular reactive oxygen species (ROS), and Ca2+ concentration were detected with cell counting kit-8 (CCK-8), flow cytometry, Chloromethyl-2'7'-dichlorofluorescein diacetate (CM-H2DCFDA) penetrant, and Fluo-4 AM staining, respectively. The binding relationship between SP1 and CPPED1 was verified by dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays. RESULTS: SP1 and CPPED1 were lowly expressed in the model rats with carotid balloon injury. Mechanistically, SP1 bound to the promoter region of CPPED1 to activate CPPED1 expression. Overexpressing SP1 or CPPED1 lowered neointimal formation and restenosis rate, thus promoting the recovery of carotid balloon injury in rats. Meanwhile, SP1 and CPPED1 upregulation reduced ROS levels, Ca2+ concentration, and apoptosis of EPCs, accompanied by accelerated EPC viability. CONCLUSIONS: SP1 or CPPED1 overexpression reduced neointimal formation and restenosis rate in carotid balloon injury.

MicroRNA-22-3p Restrains the Proliferation, Phenotypic Transformation, and Migration of Vascular Smooth Muscle Cells by Manipulating TOMM40.

microRNA (miR) -22-3p has been confirmed to be engaged in the phenotype transformation and proliferation of vascular smooth muscle cells (VSMCs), which is intimately correlated with restenosis. The current research set out to explore the detailed mechanism and function of miR-22-3p in VSMC proliferation, phenotype transformation, and migration via the translocase of outer mitochondrial membrane (TOMM40). Peripheral blood samples were acquired from patients with in-stent restenosis (ISR) after percutaneous coronary intervention (PCI), with subsequent quantitative reverse transcription (qRT) -polymerase chain reaction (PCR) and Western blot analyses of miR-22-3p and TOMM40 expression. After miR-22-3p-inhibitor, oe-TOMM40, and sh-TOMM40 were transfected into VSMCs, Cell Counting Kit (CCK) -8 assay, scratch test, and Western blot analysis were implemented to measure the VSMC proliferation, migration, and matrix metallopeptidase 9 (MMP9), α-smooth muscle actin (SMA), smooth muscle-myosin heavy chain (SM-MHC), and osteopontin (OPN) expressions, respectively. In addition, human umbilical vein endothelial cell (HUVEC) proliferation was examined by CCK-8 assay. The binding relationship between miR-22-3p and TOMM40 was assessed by dual luciferase reporter and RNA immunoprecipitation assays. The peripheral blood of patients with ISR after PCI had low expression of miR-22-3p and high expression of TOMM40. The mechanistic analysis reported the negative targeting relationship between miR-22-3p and TOMM40. Down-regulating miR-22-3p or up-regulating TOMM40 elevated the proliferation, migration, and phenotype transformation of VSMCs. miR-22-3p inhibitor had no evident impact on HUVEC proliferation. In addition, rescue assays displayed that TOMM40 silencing annulled miR-22-3p inhibition-enhanced VSMC proliferation, migration, and phenotype transformation. Conclusively, miR-22-3p could repress VSMC proliferation, phenotypic transformation, and migration by targeting TOMM40, which might be a possible treatment candidate for restenosis after PCI in patients with cardiovascular disease.

Salmonella pathogenicity island 1 knockdown confers protection against myocardial fibrosis and inflammation in uremic cardiomyopathy via down-regulation of S100 Calcium Binding Protein A8/A9 transcription.

BACKGROUND/AIM: Uremic cardiomyopathy (UCM) is a characteristic cardiac pathology that is commonly found in patients with chronic kidney disease. This study dissected the mechanism of SPI1 in myocardial fibrosis and inflammation induced by UCM through S100A8/A9. METHODS: An UCM rat model was established, followed by qRT-PCR and western blot analyses of SPI1 and S100A8/A9 expression in myocardial tissues. After alterations of SPI1 and S100A8/A9 expression in UCM rats, the blood specimens were harvested from the cardiac apex of rats. The levels of creatine phosphokinase-MB (CK-MB), blood creatinine, blood urea nitrogen (BUN), and inflammatory cytokines (interleukin [IL]-6, IL-1ß, and tumor necrosis factor-α [TNF-α]) were examined in the collected blood. Collagen fibrosis was assessed by Masson staining. The expression of fibrosis markers [transforming growth factor (TGF)-ß1, α-smooth muscle actin (SMA), Collagen 4a1, and Fibronectin], IL-6, IL-1ß, and TNF-α was measured in myocardial tissues. Chromatin immunoprecipitation and dual-luciferase reporter gene assays were conducted to test the binding relationship between SPI1 and S100A8/A9. RESULTS: S100A8/A9 and SPI1 were highly expressed in the myocardial tissues of UCM rats. Mechanistically, SPI1 bound to the promoter of S100A8/A9 to facilitate S100A8/A9 transcription. S100A8/A9 or SPI1 knockdown reduced myocardial fibrosis and inflammation and the levels of CK-MB, blood creatinine, and BUN, as well as the expression of TGF-ß1, α-SMA, Collagen 4a1, Fibronectin, IL-6, TNF-α, and IL-1ß in UCM rats. CONCLUSION: SPI1 knockdown diminished S100A8/A9 transcription, thus suppressing myocardial fibrosis and inflammation caused by UCM.

FOXO1 represses MCL1 transcription to regulate the function of vascular smooth muscle cells in intracranial aneurysm.

Intracranial aneurysm (IA) is a pathological dilation of the cerebral arteries. Vascular smooth muscle cell (VSMC) dysfunction assumes a role in IA development. In this context, this study probed the role of FOXO1 in human brain VSMC (HBVSMC) function via MCL1. FOXO1 and MCL1 expression in arterial wall tissues from IA patients and inflammatory cytokines (IL-1ß, TNF-α, and IL-6) levels in the serum of IA patients were, respectively, detected with qRT-PCR and ELISA. Pearson's correlation analysis was utilized to analyze the correlation between FOXO1 and MCL1. After FOXO1 and/or MCL1 were overexpressed in HBVSMCs, caspase-3 and Cyt-c protein expression were examined by western blot, cell proliferation by CCK-8 and EdU assays, and cell apoptosis by flow cytometry. IL-1ß, TNF-α, and IL-6 levels were assessed in the supernatant of HBVSMCs with ELISA. Dual-luciferase gene reporter and ChIP assays were conducted to evaluate the binding of FOXO1 to MCL1. FOXO1 expression was high and MCL expression was low in arterial wall tissues from IA patients, and IL-1ß, TNF-α, and IL-6 levels were high in the serum of IA patients. There was an inverse correlation between FOXO1 and MCL1 mRNA levels. Moreover, FOXO1 bound to the MCL1 promoter to decrease MCL1 transcription. In addition, FOXO1 overexpression augmented cell apoptosis, caspase-3 and Cyt-c protein expression, and IL-1ß, TNF-α, and IL-6 secretion, while reducing cell proliferation in HBVSMCs, which was abrogated by further MCL1 overexpression. FOXO1 impeded MCL1 transcription to curb HBVSMC proliferation and facilitate their apoptosis and inflammation.

Role and mechanism of the lncRNA SNHG1/miR­450b­5p/IGF1 axis in the regulation of myocardial ischemia reperfusion injury.

The increasing rates of morbidity and mortality caused by ischemic heart disease pose a serious threat to human health. Long non­coding (lnc)RNA small nucleolar RNA host gene 1 (SNHG1) has a protective effect on the myocardium. In the present study, the role of lncRNA SNHG1 in myocardial ischemia reperfusion injury (MIRI) and the underlying mechanisms were investigated. After hypoxia/reoxygenation (H/R) induction, the expression levels of lncRNA SNHG1 were detected using reverse transcription­quantitative PCR. After lncRNA SNHG1 overexpression via cell transfection, cell viability was detected using an MTT assay, apoptotic rates were detected using TUNEL staining, apoptosis­related protein expression levels were detected using western blotting and respective kits were used to measure the oxidative stress levels. The Encyclopedia of RNA Interactomes database predicted the presence of binding sites between lncRNA SNHG1 and microRNA (miR)­450b­5p, and between miR­450b­5p and insulin­like growth factor 1 (IGF1). These interactions were then verified using luciferase reporter assays. Subsequently, the regulatory mechanism underlying the lncRNA SNHG1/miR­450b­5p/IGF1 axis in MIRI was investigated by overexpressing miR­450b­5p and knocking down IGF1 expression in H/R­induced cells. Finally, the expression of PI3K/Akt signaling pathway­related proteins was detected using western blotting. lncRNA SNHG1 expression was significantly downregulated in H/R­induced AC16 cells. lncRNA SNHG1 overexpression significantly inhibited apoptosis and decreased oxidative stress levels in H/R­induced AC16 cells, which was mediated via regulation of the miR­450b­5p/IGF1 axis and activation of the PI3K/Akt signaling pathway. Therefore, the present study suggested that activation of the PI3K/Akt signaling pathway via the lncRNA SNHG1/miR­450b­5p/IGF1 axis inhibited the apoptosis and oxidative stress levels of H/R­induced AC16 cells.