HLA-B and TIMP1 as hub genes of the ventricular remodeling caused by hypertension.

RATIONALE: Myocardial fibrosis is an important pathological change that occurs during ventricular remodeling in patients with hypertension and is an important pathophysiological basis of cardiovascular disease. However, the molecular mechanism underlying this ventricular remodeling is unclear. METHODS: Bioinformatics analysis identified HLA-B and TIMP1 as hub genes in the process of myocardial fibrosis. Expression and correlation analyses of significant hub genes with ventricular remodeling were performed. Weighted gene co-expression network analysis (WGCNA) was performed to verify the role of HLA-B. ceRNA network was constructed to identify the candidate molecule drugs. Receiver operating characteristic (ROC) curves were analyzed. RESULTS: RT-qPCR was performed to verify the roles of HLA-B and TIMP1 in seven control individuals with hypertension and seven patients with hypertension and ventricular remodeling. The WGCNA showed that HLA-B was in the brown module and the correlation coefficient between HLA-B and ventricular remodeling was 0.67. Based on univariate logistic proportional regression analysis, HLA-B influences ventricular remodeling (P<0.05). RT-qPCR showed that the relative expression levels of HLA-B and TIMP1 were significantly higher in HLVR samples compared with their expression in the control group. CONCLUSIONS: HLA-B and TIMP1 might provide novel research targets for the diagnosis and treatment of HLVR.

Higher expression of TSR2 aggravating hypertension via the PPAR signaling pathway.

Hypertension is a complex disease with unknown causes. Therefore, it's crucial to deeply study its molecular mechanism. The hypertension dataset was obtained from Gene Expression Omnibus data base (GEO), and miRNA regulating central hub genes was screened via weighted gene co-expression network (DEGs) and gene set enrichment (GSEA). Cell experiments validated TSR2's role and the PPAR signaling pathway through western blotting. 500 DEGs were identified for hypertension, mainly enriched in actin cross-linking, insulin signaling, PPAR signaling, and protein localization. Eight hub genes (SEC61G, SRP14, Liy AR, NIP7, SDAD1, POLR1D, DYNLL2, TSR2) were identified. Four hub genes (LYAR, SDAD1, POLR1D, TSR2) exhibited high expression levels in the hypertensive tissue samples, while showing low expression levels in the normal tissue samples. This led us to speculate that they may have relevant regulatory effects on hypertension. When TSR2 was knocked down in the hypertension peripheral blood mononuclear cells (PBMC) model, the critical proteins in the PPAR signaling pathway (FABP, PPAR, PLTP, ME1, SCD1, CYP27, FABP1, OLR1, CPT-1, PGAR, CAP, ADIPO, MMP1, UCP1, ILK, PDK1 UBC AQP7) were downregulated. This also occurred in the hypertension peripheral blood mononuclear cells (PBMC) + TSR2_ OV model. TSR2 is highly expressed in individuals with hypertension and may play a significant role in the development of hypertension through the PPAR signaling pathway. TSR2 could serve as a molecular target for the early diagnosis and precise treatment of hypertension, providing a valuable direction for the mechanism research of this condition.

Association of serum uric acid level with intracranial aneurysms: A Mendelian randomization study.

Objective: Numerous studies have posited the involvement of serum uric acid (SUA) in the pathogenesis and progression of various cardiovascular diseases, particularly aortic aneurysms. However, the casual effect of SUA level on intracranial aneurysms (IAs) was rarely studied. Consequently, we aimed to explore the causal association between SUA and IAs using Mendelian randomization (MR) analysis. Methods: We conducted a two-sample MR analysis with SUA as the exposure variable and IAs as the outcome variable. Genome-wide association study (GWAS) datasets for SUA were acquired from the Open GWAS catalog, including 389,404 European and 129,405 East Asian individuals. The dataset for IAs was sourced from a meta-analysis of GWASs comprising 317,636 individuals across different ancestral populations (European: 7495 cases and 71,934 controls; East Asian: 3259 cases and 234,948 controls). The MR analyses were performed according to populations (European and East Asian) and IAs status [unruptured IAs (uIAs) or aneurysmal subarachnoid hemorrhage (aSAH)], respectively. The inverse variance weighted (IVW) method was employed as primary analysis to discern causal estimates. Results: Our findings revealed that an elevated genetically predicted SUA level (mg/dL) correlated with an increased risk of IAs among the European population (OR = 1.29 [95%CI:1.05-1.57], P = 0.013) and East Asian population (OR = 1.56 [95%CI: 1.27-1.92], P < 0.001). Among European individuals, subgroup analysis indicated a persistent causal association of SUA with uIAs (OR = 1.50 [95%CI: 1.08-2.08], P = 0.015) and aSAH (OR = 1.26 [95%CI: 1.00-1.60], P = 0.049). However, subgroup analysis in East Asian populations was not conducted due to the lack of separate data on uIAs and aSAH. Conclusions: Our MR analysis demonstrated a causal relationship between elevated SUA levels and an amplified risk of IAs. Further rigorous investigations are imperative to provide evidence and elucidate the underlying mechanisms.

Adrenal SGLT1 or SGLT2 as predictors of atherosclerosis under chronic stress based on a computer algorithm.

Background: Chronic stress promotes the development of atherosclerosis, causing disruptions in the body's hormone levels and changes in the structural function of organs. Objective: The purpose of this study was to investigate the pathological changes in the adrenal gland in a model of atherosclerosis under chronic stress and to verify the expression levels of Sodium-glucose cotransporter (SGLT) 1 and SGLT2 in the adrenal gland and their significance in the changes of adrenal gland. Methods: The model mice were constructed by chronic unpredictable stress, high-fat diet, and Apoe-/- knockout, and they were tested behaviorally at 0, 4, 8 and 12 weeks. The state of the abdominal artery was examined by ultrasound, and the pathological changes of the aorta and adrenal glands were observed by histological methods, and the expression levels and distribution of SGLT1 and SGLT2 in the adrenal gland were observed and analyzed by immunofluorescence and immunohistochemistry. The predictive value of SGLT1 and SGLT2 expression levels on intima-media thickness, internal diameter and adrenal abnormalities were verified by receiver operating characteristic (ROC) curves, support vector machine (SVM) and back-propagation (BP) neural network. Results: The results showed that chronic stress mice had elevated expression levels of SGLT1 and SGLT2. The model mice developed thickening intima-media and smaller internal diameter in the aorta, and edema, reticular fiber rupture, increased adrenal glycogen content in the adrenal glands. More importantly, analysis of ROC, SVM and BP showed that SGLT1 and SGLT2 expression levels in the adrenal glands could predict the above changes in the aorta and were also sensitive and specific predictors of adrenal abnormalities. Conclusion: SGLT1 and SGLT2 could be potential biomarkers of adrenal injury in atherosclerosis under chronic stress.

The Impact of COVID-19 Pandemic on the Clinical Practice Patterns in Atrial Fibrillation: A Multicenter Clinician Survey in China.

The COVID-19 pandemic has severely impacted healthcare systems worldwide. This study investigated cardiologists' opinions on how the COVID-19 pandemic impacted clinical practice patterns in atrial fibrillation (AF). A multicenter clinician survey, including demographic and clinical questions, was administered to 300 cardiologists from 22 provinces in China, in April 2022. The survey solicited information about their treatment recommendations for AF and their perceptions of how the COVID-19 pandemic has impacted their clinical practice patterns for AF. The survey was completed by 213 cardiologists (71.0%) and included employees in tertiary hospitals (82.6%) and specialists with over 10 years of clinical cardiology practice (53.5%). Most respondents stated that there were reductions in the number of inpatients and outpatients with AF in their hospital during the pandemic. A majority of participants stated that the pandemic had impacted the treatment strategies for all types of AF, although to different extents. Compared with that during the assumed non-pandemic period in the hypothetical clinical questions, the selection of invasive interventional therapies (catheter ablation, percutaneous left atrial appendage occlusion) was significantly decreased (all p < 0.05) during the pandemic. There was no significant difference in the selection of non-invasive therapeutic strategies (the management of cardiovascular risk factors and concomitant diseases, pharmacotherapy for stroke prevention, heart rate control, and rhythm control) between the pandemic and non-pandemic periods (all p > 0.05). The COVID-19 pandemic has had a profound impact on the clinical practice patterns of AF. The selection of catheter ablation and percutaneous left atrial appendage occlusion was significantly reduced, whereas pharmacotherapy was often stated as the preferred option by participating cardiologists.

SGLT1/2 as the potential biomarkers of renal damage under Apoe-/- and chronic stress via the BP neural network model and support vector machine.

Background: Chronic stress (CS) could produce negative emotions. The molecular mechanism of SGLT1 and SGLT2 in kidney injury caused by chronic stress combined with atherosclerosis remains unclear. Methods: In total, 60 C57BL/6J mice were randomly divided into four groups, namely, control (CON, n = 15), control diet + chronic stress (CON+CS, n = 15), high-fat diet + Apoe-/- (HF + Apoe-/-, n = 15), and high-fat diet + Apoe-/- + chronic stress (HF+Apoe-/- + CS, n = 15) groups. The elevated plus maze and open field tests were performed to examine the effect of chronic stress. The expression of SGLT1 and SGLT2 in the kidney was detected. The support vector machine (SVM) and back propagation (BP) neural network model were constructed to explore the predictive value of the expression of SGLT1/2 on the renal pathological changes. The receiver operating characteristic (ROC) curve analysis was used. Results: A chronic stress model and atherosclerosis model were constructed successfully. Edema, broken reticular fiber, and increased glycogen in the kidney would be obvious in the HF + Apoe-/- + CS group. Compared with the CON group, the expression of SGLT1/2 in the kidney was upregulated in the HF + Apoe-/- + CS group (P < 0.05). There existed positive correlations among edema, glycogen, reticular fiber, expression of SGLT1/2 in the kidney. There were higher sensitivity and specificity of diagnosis of SGLT1/2 for edema, reticular fiber, and glycogen in the kidney. The result of the SVM and BP neural network model showed better predictive values of SGLT1 and SGLT2 for edema and glycogen in the kidney. Conclusion: In conclusion, SGLT1/2 might be potential biomarkers of renal damage under Apoe-/- and chronic stress, which provided a potential research direction for future related explorations into this mechanism.

A Potential Target for Clinical Atherosclerosis: A Novel Insight Derived from TPM2.

Atherosclerosis (AS) is a potential inducer of numerous cardio-cerebrovascular diseases. However, little research has investigated the expression of TPM2 in human atherosclerosis samples. A total of 34 clinical samples were obtained, including 17 atherosclerosis and 17 normal artery samples, between January 2018 and April 2021. Bioinformatics analysis was applied to explore the potential role of TPM2 in atherosclerosis. Immunohistochemistry, immunofluorescence, and western blotting assays were used to detect the expression of TPM2 and α-SMA proteins. The mRNA expression levels of TPM2 and α-SMA were detected using RT-qPCR. A neural network and intima-media thickness model were constructed. A strong relationship existed between the intima-media thickness and relative protein expression of TPM2 (P<0.001, R=-0.579). The expression of TPM2 was lower in atherosclerosis than normal artery (P<0.05). Univariate logistic regression showed that TPM2 (OR=0.150, 95% CI: 0.026-0.868, P=0.034) had clear correlations with atherosclerosis. A neural network model was successfully constructed with a relativity of 0.94434. TPM2 might be an independent protective factor for arteries, and one novel biomarker of atherosclerosis.

Effect of COVID-19 Pandemic on Acute Coronary Syndrome Clinical Practice Patterns: Findings from a Multicenter Clinician Survey in China.

Background: The coronavirus disease 2019 (COVID-19) pandemic has severely affected healthcare systems around the world. This study aimed to investigate the perceptions of cardiologists regarding how the COVID-19 pandemic has affected the clinical practice patterns for acute coronary syndrome (ACS). Methods: A multicenter clinician survey was sent to 300 cardiologists working in 22 provinces in China. The survey collected demographic information and inquired about their perceptions of how the COVID-19 pandemic has affected ACS clinical practice patterns. Results: The survey was completed by 211 (70.3%) cardiologists, 82.5% of whom were employed in tertiary hospitals, and 52.1% reported more than 10 years of clinical cardiology practice. Most respondents observed a reduction in ACS inpatients and outpatients in their hospitals during the pandemic. Only 29.9% of the respondents had access to a dedicated catheter room for the treatment of COVID-19-positive ACS patients. Most respondents stated that the COVID-19 pandemic had varying degrees of effect on the treatment of acute ST-segment elevation myocardial infarction (STEMI), acute non-ST-segment elevation myocardial infarction (NSTEMI), and unstable angina. Compared with the assumed non-pandemic period, in the designed clinical questions, the selection of coronary interventional therapy for STEMI, NSTEMI, and unstable angina during the COVID-19 pandemic was significantly decreased (all p < 0.05), and the selection of pharmacotherapy was increased (all p < 0.05). The selection of fibrinolytic therapy for STEMI during the pandemic was higher than in the assumed non-pandemic period (p < 0.05). Conclusions: The COVID-19 pandemic has profoundly affected ACS clinical practice patterns. The use of invasive therapies significantly decreased during the pandemic period, whereas pharmacotherapy was more often prescribed by the cardiologists.

Citrate Synthase and OGDH as Potential Biomarkers of Atherosclerosis under Chronic Stress.

BACKGROUND: Pathological changes of the adrenal gland and the possible underlying molecular mechanisms are currently unclear in the case of atherosclerosis (AS) combined with chronic stress (CS). METHODS: New Zealand white rabbits were used to construct a CS and AS animal model. Proteomics and bioinformatics were employed to identify hub proteins in the adrenal gland related to CS and AS. Hub proteins were detected using immunohistochemistry, immunofluorescence assays, and Western blotting. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to analyze the expression of genes. In addition, a neural network model was constructed. The quantitative relationships were inferred by cubic spline interpolation. Enzymatic activity of mitochondrial citrate synthase and OGDH was detected by the enzymatic assay kit. Function of citrate synthase and OGDH with knockdown experiments in the adrenal cell lines was performed. Furthermore, target genes-TF-miRNA regulatory network was constructed. Coimmunoprecipitation (IP) assay and molecular docking study were used to detect the interaction between citrate synthase and OGDH. RESULTS: Two most significant hub proteins (citrate synthase and OGDH) that were related to CS and AS were identified in the adrenal gland using numerous bioinformatic methods. The hub proteins were mainly enriched in mitochondrial proton transport ATP synthase complex, ATPase activation, and the AMPK signaling pathway. Compared with the control group, the adrenal glands were larger and more disordered, irregular, and necrotic in the AS+CS group. The expression of citrate synthase and OGDH was higher in the AS+CS group than in the control group, both at the protein and mRNA levels (P < 0.05). There were strong correlations among the cross-sectional areas of adrenal glands, citrate synthase, and OGDH (P < 0.05) via Spearman's rho analysis, receiver operating characteristic curves, a neural network model, and cubic spline interpolation. Enzymatic activity of citrate synthase and OGDH increased under the situation of atherosclerosis and chronic stress. Through the CCK8 assay, the adrenal cell viability was downregulated significantly after the knockdown experiment of citrate synthase and OGDH. Target genes-TF-miRNA regulatory network presented the close interrelations among the predicted microRNA, citrate synthase and OGDH. After Coimmunoprecipitation (IP) assay, the result manifested that the citrate synthase and OGDH were coexpressed in the adrenal gland. The molecular docking study showed that the docking score of optimal complex conformation between citrate synthase and OGDH was -6.15 kcal/mol. CONCLUSION: AS combined with CS plays a significant role on the hypothalamic-pituitary-adrenal (HPA) axis, promotes adrenomegaly, increases the release of glucocorticoid (GC), and might enhance ATP synthesis and energy metabolism in the body through citrate synthase and OGDH gene targets, providing a potential research direction for future related explorations into this mechanism.

J-shaped relationship between serum uric acid levels and the risk of ischemic stroke in high-risk individuals: A hospital-based observational study.

OBJECTIVE: The relationship between serum uric acid (SUA) and the risk of ischemic stroke (IS) has been fully elucidated in previous studies. Therefore, we further investigated the relationship between SUA levels and the risk of IS. PATIENTS AND METHODS: 2195 patients at the Beijing Hospital, between February 2012 and May 2018, were enrolled in our hospital-based cross-sectional study. The patients were divided into an IS group and a (non-IS) control group, based on their medical records. SUA level was measured using the enzymatic uricase method. Univariate and multivariable logistic regression models were used for the analysis. RESULTS: A total of 300 patients with IS [176 men; age (mean ±â€¯SD): 71.38 ±â€¯10.66 years] and 1895 control patients [1060 men; age (mean ±â€¯SD): 66.12 ±â€¯12.04 years] were enrolled in this study. IS patients had higher concentrations of SUA, compared with control group patients [6.11 ±â€¯1.92 vs. 5.77 ±â€¯1.62 (mg/dL)]; P = 0.004). We observed a J-shaped association between SUA levels and the risk of IS. Both the univariate and multivariate logistic regression analyses found a significantly elevated risk of IS in the bottom and upper SUA levels both in quartiles and deciles, compared with the intermediate SUA levels. CONCLUSION: These results indicate a J-shaped, independent association between SUA levels and the risk of IS in high-risk individuals.

Lipoprotein-Associated Phospholipase A2 Activity and Mass as Independent Risk Factor of Stroke: A Meta-Analysis.

BACKGROUND: The association between lipoprotein-associated phospholipase A2 (Lp-PLA2) and stroke risk is inconsistent. We conducted a meta-analysis to determine whether elevated Lp-PLA2 is a risk factor for stroke. METHODS: Studies were included if they reported Lp-PLA2 mass and/or activity levels and adjusted risk estimates of stroke. The primary outcome was overall stroke incidence. The combined results were shown as relative risks (RRs) with 95% confidence intervals (CI) for per 1 standard deviation (SD) higher value of Lp-PLA2 and the highest versus lowest Lp-PLA2 category. RESULTS: Twenty-two studies involving 157,693 participants were included for analysis. After adjusting for conventional risk factors, the RRs for overall stroke with 1 SD higher Lp-PLA2 activity and mass were 1.07 (95% CI 1.02-1.13) and 1.11 (95% CI 1.04-1.19), respectively. The RRs of ischemic stroke with 1 SD higher Lp-PLA2 activity and mass were 1.08 (95% CI 1.01-1.15) and 1.11 (95% CI 1.02-1.22), respectively. When comparing the highest and lowest levels of Lp-PLA2, the RRs of stroke for Lp-PLA2 activity and mass were 1.26 (95% CI 1.03-1.54) and 1.56 (95% CI 1.21-2.00), respectively. Finally, when comparing the highest and lowest levels of Lp-PLA2, the pooled RRs of ischemic stroke for Lp-PLA2 activity and mass were 1.29 (95% CI 1.07-1.56) and 1.68 (95% CI 1.12-2.53), respectively. CONCLUSIONS: Elevated baseline Lp-PLA2 levels, detected either by activity or mass, are associated with increased stroke risk.

Identification of biomarkers in macrophages of atherosclerosis by microarray analysis.

BACKGROUND: Atherosclerotic cardiovascular disease (ASCVD) refers to a series of diseases caused by atherosclerosis (AS). It is one of the most important causes of death worldwide. According to the inflammatory response theory, macrophages play a critical role in AS. However, the potential targets associated with macrophages in the development of AS are still obscure. This study aimed to use bioinformatics tools for screening and identifying molecular targets in AS macrophages. METHODS: Two expression profiling datasets (GSE7074 and GSE9874) were obtained from the Gene Expression Omnibus dataset, and differentially expressed genes (DEGs) between non-AS macrophages and AS macrophages were identified. Functional annotation of the DEGs was performed by analyzing the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases. STRING and Cytoscape were employed for constructing a protein-protein interaction network and analyzing hub genes. RESULTS: A total of 98 DEGs were distinguished between non-AS macrophages and AS macrophages. The functional variations in DEGs were mainly enriched in response to hypoxia, respiratory gaseous exchange, protein binding, and intracellular, ciliary tip, early endosome membrane, and Lys63-specific deubiquitinase activities. Three genes were identified as hub genes, including KDELR3, CD55, and DYNC2H1. CONCLUSION: Hub genes and DEGs identified by using microarray techniques can be used as diagnostic and therapeutic biomarkers for AS.