The roles of B cells in cardiovascular diseases.

Damage to the heart can start the repair process and cause cardiac remodeling. B cells play an important role in this process. B cells are recruited to the injured place and activate cardiac remodeling through secreting antibodies and cytokines. Different types of B cells showed specific functions in the heart. Among all types of B cells, heart-associated B cells play a vital role in the heart by secreting TGFß1. B cells participate in the activation of fibroblasts and promote cardiac fibrosis. Four subtypes of B cells in the heart revealed the relationship between the B cells' heterogeneity and cardiac remodeling. Many cardiovascular diseases like atherosclerosis, heart failure (HF), hypertension, myocardial infarction (MI), and dilated cardiomyopathy (DCM) are related to B cells. The primary mechanisms of these B cell-related activities will be discussed in this review, which may also suggest potential novel therapeutic targets.

Integrated analysis reveals ceRNA network of cardiac remodeling by SGLT2 inhibitor in middle-aged hypertensive rats.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) represent an innovative class of antidiabetic agents that have demonstrated promise in mitigating cardiac remodeling. However, the transcriptional regulatory mechanisms underpinning their impact on blood pressure and the reversal of hypertension-induced cardiac remodeling remain largely unexplored. Given this context, our study concentrated on comparing the cardiac expression profiles of lncRNAs and mRNAs between Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). To validate our results, we performed blood pressure measurements, tissue staining, and qRT-PCR. The treatment led to a significant reduction in systolic blood pressure and improved cardiac remodeling by reducing myocardial fibrosis and regulating the inflammatory response. Our examination disclosed that ventricular tissue mRNA, regulated by hypertension, was primarily concentrated in the complement and coagulation cascades and cytokine-cytokine receptor interactions. Compared with SHR, the SGLT2i treatment group was associated with myocardial contraction. Investigation into the lncRNA-mRNA regulatory network and competing endogenous RNA (ceRNA) network suggested that the potential roles of these differentially expressed (DE) lncRNAs and mRNAs were tied to processes such as collagen fibril organization, inflammatory response, and extracellular matrix (ECM) modifications. We found that the expression of Col3a1, C1qa, and lncRNA NONRATT007139.2 were altered in the SHR group and that SGLT2i treatment reversed these changes. Our results suggest that dapagliflozin effectively reverses hypertension-induced myocardial remodeling through a lncRNA-mRNA transcriptional regulatory network, with immune cell-mediated ECM deposition as a potential regulatory target. This underlines the potentiality of SGLT2i and genes related to immunity as promising targets for the treatment of hypertension.

Single-cell RNA sequencing reveals the transcriptional heterogeneity of Tbx18-positive cardiac cells during heart development.

The T-box family transcription factor 18 (Tbx18) has been found to play a critical role in regulating the development of the mammalian heart during the primary stages of embryonic development while the cellular heterogeneity and landscape of Tbx18-positive (Tbx18+) cardiac cells remain incompletely characterized. Here, we analyzed prior published single-cell RNA sequencing (scRNA-seq) mouse heart data to explore the heterogeneity of Tbx18+ cardiac cell subpopulations and provide a comprehensive transcriptional landscape of Tbx18+ cardiac cells during their development. Bioinformatic analysis methods were utilized to identify the heterogeneity between cell groups. Based on the gene expression characteristics, Tbx18+ cardiac cells can be classified into a minimum of two distinct cell populations, namely fibroblast-like cells and cardiomyocytes. In terms of temporal heterogeneity, these cells exhibit three developmental stages, namely the MEM stage, ML_P0 stage, and P stage Tbx18+ cardiac cells. Furthermore, Tbx18+ cardiac cells encompass several cell types, including cardiac progenitor-like cells, cardiomyocytes, and epicardial/stromal cells, as determined by specific transcriptional regulatory networks. The scRNA-seq results revealed the involvement of extracellular matrix (ECM) signals and epicardial epithelial-to-mesenchymal transition (EMT) in the development of Tbx18+ cardiac cells. The utilization of a lineage-tracing model served to validate the crucial function of Tbx18 in the differentiation of cardiac cells. Consequently, these findings offer a comprehensive depiction of the cellular heterogeneity within Tbx18+ cardiac cells.

Exploration and validation of signature genes and immune associations in septic cardiomyopathy.

An early and accurate diagnosis of septic cardiomyopathy is vital for improving the overall prognosis of sepsis. In our research, we aimed to identify signature genes and their immune connections in septic cardiomyopathy. By analyzing the mouse myocardial transcriptome from sepsis induced by cecum ligation and puncture (CLP), we identified four distinct k-means clusters. Further analysis of human myocardial datasets using Weighted Gene Co-expression Network Analysis (WGCNA) revealed a strong correlation between the MEturquoise module and septic cardiomyopathy (cor = 0.79, p < .001). Through the application of Cytoscape plug-in MCODE and comprehensive analysis, we pinpointed two signature genes, THBS1 and TIMP1. These genes demonstrated significant involvement in immune cell infiltration, as detected by CIBERSORT, and displayed promising prognostic potential as validated by external datasets. Our experimental validation confirmed the up-regulation of both THBS1 and TIMP1 in septic murine hearts, underscoring their positive association with septic cardiomyopathy.

Single-cell and spatial heterogeneity landscapes of mature epicardial cells.

Tbx18, Wt1, and Tcf21 have been identified as epicardial markers during the early embryonic stage. However, the gene markers of mature epicardial cells remain unclear. Single-cell transcriptomic analysis was performed with the Seurat, Monocle, and CellphoneDB packages in R software with standard procedures. Spatial transcriptomics was performed on chilled Visium Tissue Optimization Slides (10x Genomics) and Visium Spatial Gene Expression Slides (10x Genomics). Spatial transcriptomics analysis was performed with Space Ranger software and R software. Immunofluorescence, whole-mount RNA in situ hybridization and X-gal staining were performed to validate the analysis results. Spatial transcriptomics analysis revealed distinct transcriptional profiles and functions between epicardial tissue and non-epicardial tissue. Several gene markers specific to postnatal epicardial tissue were identified, including Msln, C3, Efemp1, and Upk3b. Single-cell transcriptomic analysis revealed that cardiac cells from wildtype mouse hearts (from embryonic day 9.5 to postnatal day 9) could be categorized into six major cell types, which included epicardial cells. Throughout epicardial development, Wt1, Tbx18, and Upk3b were consistently expressed, whereas genes including Msln, C3, and Efemp1 exhibited increased expression during the mature stages of development. Pseudotime analysis further revealed two epicardial cell fates during maturation. Moreover, Upk3b, Msln, Efemp1, and C3 positive epicardial cells were enriched in extracellular matrix signaling. Our results suggested Upk3b, Efemp1, Msln, C3, and other genes were mature epicardium markers. Extracellular matrix signaling was found to play a critical role in the mature epicardium, thus suggesting potential therapeutic targets for heart regeneration in future clinical practice.

RNA-Seq transcriptomic landscape profiling of spontaneously hypertensive rats treated with a sodium-glucose cotransporter 2 (SGLT2) inhibitor.

BACKGROUND: Sodium-glucose co-transporter-2 inhibitor (SGLT2i) are antihyperglycemic medications that reduce cardiovascular disease (CVD) and improve chronic kidney disease prognosis in patients with diabetes mellitus. The specific impact of SGLT2i treatment on hypertensive individuals, however, remains to be established. This underscores the need for systematic efforts to profile the molecular landscape associated with SGLT2i administration. METHODS: We conducted a detailed RNA-sequencing (RNA-Seq)-based exploration of transcriptomic changes in response to empagliflozin in eight different tissues (i.e., atrium, aorta, ventricle, white adipose, brown adipose, kidney, lung, and brain) from a male rat model of spontaneously hypertension. Corresponding computational analyses (i.e., clustering, differentially-expressed genes [DEG], and functional association) were performed to analyze these data. Blood pressure measurements, tissue staining studies and RT-qPCR were performed to validate our in silico findings. RESULTS: We discovered that empagliflozin exerted potent transcriptomic effects on various tissues, most notably the kidney, white adipose, and lung in spontaneously hypertension rats (SHR). The functional enrichment of DEGs indicated that empagliflozin may regulate blood pressure, blood glucose and lipid homeostasis in SHR. Consistent with our RNA-Seq findings, immunohistochemistry and qPCR analyses revealed decreased renal expression of mitogen-activated protein kinase 10 (MAPK10) and decreased pulmonary expression of the proinflammatory factors Legumain and cathepsin S (CTSS) at 1 month of empagliflozin administration. Notably, immunofluorescence experiments showed increased expression of the AMP-activated protein kinases Prkaa1 and Prkaa2 in white adipose tissue of SHR following empagliflozin therapy. Furthermore, the transcriptomic signatures of the blood pressure-lowing effect by empagliflozin were experimentally validated in SHR. CONCLUSIONS: This study provided an important resource of the effects of empagliflozin on various tissues of SHRs. We identified tissue-specific and tissue-enriched transcriptomic signatures, and uncovered the beneficial effects of empagliflozin on hypertension, weight gain and inflammatory response in validated experiments.

RNA-Seq transcriptome analysis of renal tissue from spontaneously hypertensive rats revealed renal protective effects of dapagliflozin, an inhibitor of sodium-glucose cotransporter 2.

Hypertensive nephropathy (HTN) is a common complication of hypertension. Although various agents for treatment of hypertension exert significant effects, there is currently no effective treatment for hypertensive nephropathy. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, such as dapagliflozin (DAPA), are a new class of hypoglycemic agents shown to improve the prognosis of patients with chronic kidney disease and diabetes mellitus. However, the mechanisms underlying the protective effects of DAPA remain unclear. RNA-sequencing (RNA-Seq)-based computational analysis was conducted to explore the transcriptomic changes to spontaneously hypertensive rats (SHRs) treated with DAPA for 8 weeks. Differentially expressed genes in SHRs were related to dysregulation of lipid metabolism, oxidation-reduction reaction, immunity and inflammation in HTN. Transcriptome analysis showed that 8 weeks of DAPA therapy exerted protective effects on the renal tissues of SHRs through the lysosomal, phagosomal, and autophagic pathways. VENN diagram analysis identified Zinc finger and BTB domain-containing 20 (Zbtb20) as the potential target of DAPA therapy. Consistent with the RNA-Seq findings, real-time quantitative PCR and immunohistochemical analyses revealed increased expression of Zbtb20 in the renal tissues of SHRs, whereas expression was decreased following 8 weeks of DAPA administration. The results of this study clarified the transcriptome signature of HTN and the beneficial effects of DAPA on renal tissues by alleviating dysregulation of metabolic processes and reducing inflammation.

Single-cell and spatial transcriptomics: Advances in heart development and disease applications.

Current transcriptomics technologies, including bulk RNA-seq, single-cell RNA sequencing (scRNA-seq), single-nucleus RNA-sequencing (snRNA-seq), and spatial transcriptomics (ST), provide novel insights into the spatial and temporal dynamics of gene expression during cardiac development and disease processes. Cardiac development is a highly sophisticated process involving the regulation of numerous key genes and signaling pathways at specific anatomical sites and developmental stages. Exploring the cell biological mechanisms involved in cardiogenesis also contributes to congenital heart disease research. Meanwhile, the severity of distinct heart diseases, such as coronary heart disease, valvular disease, cardiomyopathy, and heart failure, is associated with cellular transcriptional heterogeneity and phenotypic alteration. Integrating transcriptomic technologies in the clinical diagnosis and treatment of heart diseases will aid in advancing precision medicine. In this review, we summarize applications of scRNA-seq and ST in the cardiac field, including organogenesis and clinical diseases, and provide insights into the promise of single-cell and spatial transcriptomics in translational research and precision medicine.

Stroke-induced hexokinase 2 in circulating monocytes exacerbates vascular inflammation and atheroprogression.

BACKGROUND: Stroke accelerates inflammatory monocyte recruitment to the endothelium and consequent atheroprogression via high-mobility group box 1-receptor for advanced glycation end products signaling. Notably, Hmgb1 interacts with multiple toll-like receptors (TLRs) and promotes TLR4-mediated proinflammatory myeloid cell activation. Therefore, TLR-associated mechanism(s) within monocytes may play a role in Hmgb1-driven poststroke atheroprogression. OBJECTIVES: We aimed to elucidate the TLR-associated mechanism(s) within monocytes that contribute to stroke-induced exacerbation of atherosclerotic disease. METHODS: A weighted gene coexpression network analysis on the whole blood transcriptomes of stroke model mice identified hexokinase 2 (HK2) as a key gene associated with TLR signaling in ischemic stroke. We conducted a cross-sectional analysis of monocyte HK2 levels in patients with ischemic stroke patients. We performed in vitro and in vivo studies using high-cholesterol diet-fed myeloid-specific Hk2-null ApoE-/- (ApoE-/-;Hk2ΔMφ) mice and ApoE-/-;Hk2fl/fl controls. RESULTS: We found markedly higher monocyte HK2 levels in patients with ischemic stroke patients during the acute and subacute phases poststroke. Similarly, stroke model mice displayed a profound increase in monocyte Hk2 levels. Using aortas and aortic valve samples collected from high-cholesterol diet-fed ApoE-/-;Hk2ΔMφ mice and ApoE-/-;Hk2fl/fl controls, we found that stroke-induced monocyte Hk2 upregulation enhanced poststroke atheroprogression and inflammatory monocyte recruitment to the endothelium. Stroke-induced monocyte Hk2 upregulation induced inflammatory monocyte activation, systemic inflammation, and atheroprogression via Il-1ß. Mechanistically, we demonstrated that stroke-induced monocyte Hk2 upregulation was dependent upon Hmgb1-driven p38-dependent hypoxia-inducible factor-1α stabilization. CONCLUSION: Stroke-induced monocyte Hk2 upregulation is a key mechanism underlying poststroke vascular inflammation and atheroprogression.

Sinus node dysfunction and atrial fibrillation-Relationships, clinical phenotypes, new mechanisms, and treatment approaches.

Although the anatomical basis of the pathogenesis of sinus node dysfunction (SND) and atrial fibrillation (AF) is located primarily in the left and right atria, increasing evidence suggests a strong correlation between SND and AF, in terms of both clinical presentation and formation mechanisms. However, the exact mechanisms underlying this association are unclear. The relationship between SND and AF may not be causal, but is likely to involve common factors and mechanisms, including ion channel remodeling, gap junction abnormalities, structural remodeling, genetic mutations, neuromodulation abnormalities, the effects of adenosine on cardiomyocytes, oxidative stress, and viral infections. Ion channel remodeling manifests primarily as alterations in the "funny" current (If) and Ca2+ clock associated with cardiomyocyte autoregulation, and gap junction abnormalities are manifested primarily as decreased expression of connexins (Cxs) mediating electrical impulse propagation in cardiomyocytes. Structural remodeling refers primarily to fibrosis and cardiac amyloidosis (CA). Some genetic mutations can also cause arrhythmias, such as SCN5A, HCN4, EMD, and PITX2. The intrinsic cardiac autonomic nervous system (ICANS), a regulator of the heart's physiological functions, triggers arrhythmias.In addition, we discuss arrhythmias caused by viral infections, notably Coronavirus Disease 2019 (COVID-19). Similarly to upstream treatments for atrial cardiomyopathy such as alleviating CA, ganglionated plexus (GP) ablation acts on the common mechanisms between SND and AF, thus achieving a dual therapeutic effect.

Dapagliflozin attenuates myocardial remodeling in hypertension by activating the circadian rhythm signaling pathway.

Sodium-glucose cotransporter 2 inhibitor (SGLT2i) is a new kind of antidiabetic drug which has shown beneficial effects in reducing heart failure-related hospitalization and cardiovascular-related mortality. The mechanisms are complicated. Our study aimed to investigate the effects of dapagliflozin on the myocardium of spontaneously hypertensive rats (SHRs) without heart failure. Wistar-Kyoto rats were used as normal controls. SHRs were randomly divided into the SHR group and the -treated group. After 8 weeks of dapagliflozin treatment, the morphology of heart tissues was examined. The mRNA expression profiles were identified via RNA sequencing (RNA-Seq). Various analysis methods were used to find the differentially expressed genes (DEGs) to predict gene function and coexpression. After dapagliflozin treatment, systolic blood pressure was significantly reduced compared with that in the SHR group. Myocardial remodeling was ameliorated compared with that in the SHR group. After dapagliflozin intervention, 75 DEGs (|log2-fold change | > 0 and Q value < 0.05) were identified in the heart tissues compared to the SHR group. Quantitative real-time PCR analysis confirmed that the expression of the circadian rhythm genes Per3, Bhlhe41, and Nr1d1 was significantly upregulated, while the results were coincident with the RNA-Seq results. Dapagliflozin may effectively inhibit myocardial remodeling and regulate blood pressure. The mechanisms may be related to the activation of the circadian rhythm signaling pathway.

Transcriptomic profile analysis of the left atrium in spontaneously hypertensive rats in the early stage.

Left atrial remodeling, characterized by enlargement and hypertrophy of the left atrium and increased fibrosis, was accompanied by an increased incidence of atrial fibrillation. While before morphological changes at the early stage of hypertension, how overloaded hypertension influences the transcriptomic profile of the left atrium remains unclear. Therefore, RNA-sequencing was performed to define the RNA expressing profiles of left atrium in spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats as a control group. We also compared the changes in the RNA expression profiles in SHRs treated with an angiotensin receptor blocker (ARB) and angiotensin receptor-neprilysin inhibitor (ARNI) to assess the distinct effects on the left atrium. In total, 1,558 differentially expressed genes were found in the left atrium between WKY rats and SHRs. Bioinformatics analysis showed that these mRNAs could regulate upstream pathways in atrial remodeling through atrial fibrosis, inflammation, electrical remodeling, and cardiac metabolism. The regulated transcripts detected in the left atrial tissue in both the ARB-treated and ARNI-treated groups were related to metabolism. In contrast to the ARB-treated rates, the transcripts in ARNI-treated rats were mapped to the cyclic guanosine monophosphate-protein kinase G signaling pathway.

Correlation between plasma sphingosine-1-phosphate and the occurrence and severity of coronary heart disease in postmenopausal women.

OBJECTIVE: Sphingosine-1-phosphate (S1P) is a bioactive sphingosine with antiatherosclerotic effects. The incidence of coronary heart disease (CHD) increases significantly among women after menopause. We explored the relationship between plasma S1P levels and the occurrence and severity of CHD in postmenopausal women. METHODS: Postmenopausal women admitted to our hospital for coronary angiography because of chest pain-like symptoms were included in our study. By 1:1 age matching (age difference ≤5 y), 166 women in the CHD group and control group were enrolled. The plasma S1P concentration was determined, and the Gensini score was calculated to decide the severity of CHD. RESULTS: Plasma S1P levels were significantly lower in the CHD group of postmenopausal women ( P < 0.001). S1P (odds ratio, 0.952; 95% CI, 0.934-0.970) was an independent predictor of the occurrence of CHD in postmenopausal women. The area under the curve for S1P to predict the occurrence of CHD was 0.653 (95% CI, 0.595-0.712), and the cutoff value was 96.89 ng/mL. The plasma S1P level was the lowest in the high-tertile group of the Gensini score ( P < 0.001), and the plasma S1P (odds ratio, 0.948; 95% CI, 0.926-0.970) was an independent predictor of a high Gensini score in postmenopausal women with CHD. CONCLUSIONS: Plasma S1P is an independent risk factor of the occurrence and severity of CHD in postmenopausal women. The occurrence and aggravation of CHD in postmenopausal women may be related to levels of S1P.

Cold Pressor Test in Primary Hypertension: A Cross-Sectional Study.

Objectives: To investigate the characteristics of patients with primary hypertension who had positive responses to the cold pressor test (CPT). Methods: This cross-sectional study was conducted between November 2018 to November 2019, and the CPT was performed in patients with primary hypertension in 48 hospitals. The demographic characteristics and complications were collected through a questionnaire and physical examinations. A 12-month follow-up was conducted to identify the occurrence of the following events: a) all-cause mortality; b) myocardial infarction; c) stroke; d) hospitalized for heart failure. Results: The CPT was positive in 30.7% of the patients. Compared with the negative CPT group, the positive CPT group was associated with a lower rate of blood pressure control, and was more likely to have a high salt diet, diabetes, hyperuricemia, left ventricular wall thickening, carotid plaques, coronary heart disease and heart failure. A high-salt diet (OR = 1.228, 95%CI: 1.037-1.456) was found to be correlated with the positive result of CPT. Among patients in the positive CPT group, those using diuretics had a significantly higher rate of blood pressure control than those not using diuretics (54.6 vs.42.6%, x2 = 6.756, P = 0.009). After a 12-month follow-up, the incidence of heart failure in the positive CPT group was significantly higher than that in the negative CPT group (7.35 vs.5.01%, x2 = 3.945, P = 0.047). Conclusions: Patients with positive responses to the CPT had lower rates of BP control and a high risk of heart failure, which may be related to their preference for a high-salt diet. The use of diuretics helps to better control blood pressure in those patients.

Antibodies Can Last for More Than 1 Year After SARS-CoV-2 Infection: A Follow-Up Study From Survivors of COVID-19.

Background: COVID-19 is a global pandemic. The prevention of SARS-CoV-2 infection and the rehabilitation of survivors are currently the most urgent tasks. However, after patients with COVID-19 are discharged from the hospital, how long the antibodies persist, whether the lung lesions can be completely absorbed, and whether cardiopulmonary abnormalities exist remain unclear. Methods: A total of 56 COVID-19 survivors were followed up for 12 months, with examinations including serum virus-specific antibodies, chest CT, and cardiopulmonary exercise testing. Results: The IgG titer of the COVID-19 survivors decreased gradually, especially in the first 6 months after discharge. At 6 and 12 months after discharge, the IgG titer decreased by 68.9 and 86.0%, respectively. The IgG titer in patients with severe disease was higher than that in patients with non-severe disease at each time point, but the difference did not reach statistical significance. Among the patients, 11.8% were IgG negative up to 12 months after discharge. Chest CT scans showed that at 3 and 10 months after discharge, the lung opacity had decreased by 91.9 and 95.5%, respectively, as compared with that at admission. 10 months after discharge, 12.5% of the patients had an opacity percentage >1%, and 18.8% of patients had pulmonary fibrosis (38.5% in the severe group and 5.3% in the non-severe group, P < 0.001). Cardiopulmonary exercise testing showed that 22.9% of patients had FEV1/FVC%Pred <92%, 17.1% of patients had FEV1%Pred <80%, 20.0% of patients had a VO2 AT <14 mlO2/kg/min, and 22.9% of patients had a VE/VCO2 slope >30%. Conclusions: IgG antibodies in most patients with COVID-19 can last for at least 12 months after discharge. The IgG titers decreased significantly in the first 6 months and remained stable in the following 6 months. The lung lesions of most patients with COVID-19 can be absorbed without sequelae, and a few patients in severe condition are more likely to develop pulmonary fibrosis. Approximately one-fifth of the patients had cardiopulmonary dysfunction 6 months after discharge.

The Transcription Factor SUB1 Is a Master Regulator of the Macrophage TLR Response in Atherosclerosis.

Toll-like receptor 2 and 4 (TLR2, TLR4) signaling is implicated in atherosclerotic plaque formation. The two-stage master regulator Virtual Inference of Protein-activity by Enriched Regulon (VIPER) analysis of macrophage TLR2 and TLR4 signature genes integrated with coexpression network genes derived from 371 patient-derived carotid specimens identifies activated RNA polymerase II transcriptional coactivator p15 (SUB1/Sub1, PC4) as a master regulon in the atherogenic TLR response. It is found that TLR2 and TLR4 signaling is proinflammatory and proatherosclerotic in chow-fed apolipoprotein E-deficient (ApoE-/- ) mice. Through transgenic myeloid-specific Sub1 knockout in ApoE-/- mice, it is discovered that these proatherosclerotic effects of TLR2 and TLR4 signaling are mediated by Sub1. Sub1 knockout in macrophages enhances anti-inflammatory M2 macrophage polarization and cholesterol efflux. Irradiated low density lipoprotein receptor-deficient (Ldlr-/- ) mice transplanted with Sub1-/- murine bone marrow display reduced atherosclerosis. Promoter analysis reveals Sub1-dependent activation of interferon regulatory factor 1 (Irf1) transcription in a casein kinase 2 (Ck2)-dependent manner, and Sub1-knockout macrophages display decreased Irf1 expression. Artificial Irf1 overexpression in Sub1-knockout macrophages enhances proinflammatory M1 skewing and lowers cholesterol clearance. In conclusion, the TLR master regulon Sub1, and its downstream effect on the transcription factor Irf1, promotes a proinflammatory M1 macrophage phenotype and enhances atherosclerotic burden in vivo.

Tbx18-positive cells-derived myofibroblasts contribute to renal interstitial fibrosis via transforming growth factor-ß signaling.

It has been demonstrated that the T-box family transcription factor 18 (Tbx18) -positive cells give rise to renal mesenchymal cells and contribute to the development of the urinary system. However, it is unclear whether Tbx18-positive cells are the origin of the myofibroblasts during renal fibrosis. The present study aimed to determine the contribution of Tbx18-positive cells in kidney fibrosis and their underlying mechanism. We show that Tbx18-positive cells contribute to the development of the urinary system, especially renal fibroblasts. Following unilateral ureteral obstruction (UUO), genetic fate tracing results demonstrated that Tbx18-positive cells not only proliferate but also expand and differentiate into fibroblasts and myofibroblasts, indicating that they may act as profibrotic progenitors. Cell culture results suggest that transforming growth factor (TGF)-ß promotes Tbx18-positive cells differentiation into myofibroblasts and assist their contribution to kidney fibrosis. Overall, the present study demonstrated that Tbx18-positive cells may act as profibrotic progenitor cells in a pathological condition of UUO-induced injury. Moreover, TGF-ß may play a role in differentiation of Tbx18-positive cells into myofibroblasts in kidney fibrosis. These findings may provide a potential target on Tbx18-positive myofibroblast progenitors in the treatment of renal fibrosis.

The effects of lipid-lowering therapy on coronary plaque regression: a systematic review and meta-analysis.

To assess the influence of lipid-lowering therapy on coronary plaque volume, and to identify the LDL and HDL targets for plaque regression to provide a comprehensive overview. The databases searched (from inception to 15 July 2020) to identify prospective studies investigating the impact of lipid-lowering therapy on coronary plaque volume and including quantitative measurement of plaque volume by intravascular ultrasound after treatment. Thirty-one studies that included 4997 patients were selected in the final analysis. Patients had significantly lower TAV (SMD: 0.123 mm3; 95% CI 0.059, 0.187; P = 0.000) and PAV (SMD: 0.123%; 95% CI 0.035, 0.212; P = 0.006) at follow-up. According to the subgroup analyses, TAV was significantly reduced in the LDL < 80 mg/dL and HDL > 45 mg/dL group (SMD: 0.163 mm3; 95% CI 0.092, 0.234; P = 0.000), and PAV was significantly reduced in the LDL < 90 mg/dL and HDL > 45 mg/dL group (SMD: 0.186%; 95% CI 0.081, 0.291; P = 0.001).Thirty-one studies that included 4997 patients were selected in the final analysis. Patients had significantly lower TAV (SMD: 0.123 mm3; 95% CI 0.059, 0.187; P = 0.000) and PAV (SMD: 0.123%; 95% CI 0.035, 0.212; P = 0.006) at follow-up. According to the subgroup analyses, TAV was significantly reduced in the LDL < 80 mg/dL and HDL > 45 mg/dL group (SMD: 0.163 mm3; 95% CI 0.092, 0.234; P = 0.000), and PAV was significantly reduced in the LDL < 90 mg/dL and HDL > 45 mg/dL group (SMD: 0.186%; 95% CI 0.081, 0.291; P = 0.001). Our meta-analysis suggests that not only should LDL be reduced to a target level of < 80 mg/dL, but HDL should be increased to a target level of > 45 mg/dL to regress coronary plaques.Trial Registration PROSPERO identifier: CRD42019146170.

Inhibition of Notch Signaling Promotes the Differentiation of Epicardial Progenitor Cells into Adipocytes.

BACKGROUND: The role of Notch signaling pathway in the differentiation of epicardial progenitor cells (EPCs) into adipocytes is unclear. The objective is to investigate the effects of Notch signaling on the differentiation of EPCs into adipocytes. METHODS: Frozen sections of C57BL/6J mouse hearts were used to observe epicardial adipose tissue (EAT), and genetic lineage methods were used to trace EPCs. EPCs were cultured in adipogenic induction medium with Notch ligand jagged-1 or γ-secretase inhibitor DAPT. The adipocyte markers, Notch signaling, and adipogenesis transcription factors were determined. RESULTS: There was EAT located at the atrial-ventricular groove in mouse. By using genetic lineage tracing methods, we found that EPCs were a source of epicardial adipocytes. EPCs had lipid droplet accumulation, and the expression of adipocyte markers FABP-4 and perilipin-1 was upregulated under adipogenic induction. Activating the Notch signaling with jagged-1 attenuated the adipogenic differentiation of EPCs and downregulated the key adipogenesis transcription factor peroxisome proliferator activated receptor-γ (PPAR-γ), while inhibiting the signaling promoted adipogenic differentiation and upregulated PPAR-γ. When blocking PPAR-γ, the role of Notch signaling in promoting adipogenic differentiation was inhibited. CONCLUSIONS: EPCs are a source of epicardial adipocytes. Downregulation of the Notch signaling pathway promotes the differentiation of EPCs into adipocytes via PPAR-γ.

SGLT2i versus ARNI in heart failure with reduced ejection fraction: a systematic review and meta-analysis.

AIMS: This study aimed to determine the effects of sodium-glucose cotransporter-2 inhibitor (SGLT2i) in heart failure with reduced ejection fraction (HFrEF), compare the effect of SGLT2i with angiotensin receptor neprilysin inhibitor (ARNI), and find whether combination of SGLT2i and ARNI is better than monotherapy. METHODS AND RESULTS: Embase, Medline, and Cochrane Central Registry of Controlled Trials were searched for randomized controlled trials evaluating SGLT2i or ARNI in HFrEF. And a total of six trials were included. SGLT2i was found to significantly reduce the risk of cardiovascular death or hospitalization for heart failure by 27% [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.67-0.80], hospitalization for heart failure by 31% (HR 0.69, 95% CI 0.62-0.77), cardiovascular death by 16% (HR 0.84, 95% CI 0.74-0.95), and all-cause death by 16% (HR 0.84, 95% CI 0.75-0.94) in HFrEF only with a statistically higher risk of genital infection (risk ratio (RR) 2.78, 95% CI 1.46-5.29). The reduction in cardiovascular death or hospitalization for heart failure was of similar magnitude in patients with or without diabetes mellitus (HR 0.71, 95% CI 0.64-0.80 vs. HR 0.75, 95% CI 0.65-0.87) using SGLT2i. Indirect treatment comparison showed that SGLT2i and ARNI had similar effects on primary outcome (HR 0.93, 95% CI 0.82-1.06). And combination of SGLT2i and ARNI achieved a better prognosis performance (HR 0.68, 95% CI 0.53-0.89) compared with ARNI monotherapy. CONCLUSIONS: SGLT2i could safely reduce cardiovascular death or hospitalization for heart failure in HFrEF regardless of diabetes mellitus status. SGLT2i and ARNI demonstrate similar effects, while combination of SGLT2i and ARNI results in a better cardiovascular protective effect.